AGE-RELATED FEATURES OF LIVER CHANGES DURING INTERMITTENT FASTING (LITERATURE REVIEW)
Abstract
The increase in average life expectancy in the world and the corresponding increase in the prevalence of age-related diseases make it necessary for modern medicine to seek new approaches to their prevention and treatment. Intermittent fasting (IF) can be proposed as an effective method not only for weight loss and treatment of metabolic diseases, but also for maintaining the healthy state of internal organs, particularly the liver, during aging.
Materials and methods. An analysis of literary sources was conducted to investigate modern ideas about the role of various IF methods in maintaining a healthy liver in people of different age groups.
Results. Aging of liver tissue is accompanied by the gradual development of steatosis and fibrosis, which, under certain living conditions, nutrition, and the presence of metabolic disorders, leads to the development of chronic liver diseases.
Intermittent fasting is based on various schemes of alternating fasting and meal times, which lead to the following changes in liver metabolism: activation of signaling pathways of the adaptive cellular response to stress, which improve mitochondrial function; glucose regulation, DNA repair, increased stress resistance, activation of lipophagy in hepatocytes, suppression of inflammation, and increased regulation of autophagy. IF has protective and rejuvenating effects and improves the functionality and composition of biomolecules, which are responsible for homeostatic, energetic, and remodeling processes in liver cells.
Conclusions. IF is an effective and affordable method of non-drug treatment of metabolic diseases through the restoration and rejuvenation of the main metabolic organ of the body – the liver. The positive effect of IF on liver metabolic processes is to reduce body weight, decrease blood pressure and the level of inflammatory markers in the body, improve insulin resistance and lipid profile, and slow down aging processes.
IF helps reduce the risk of developing diseases such as type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease, and certain types of cancer, and improves the body's metabolic health. IF is a promising and relevant direction in combating the effects of liver aging, which opens up new opportunities for maintaining health in elderly people.
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Papatheodoridi AM, Chrysavgis L, Koutsilieris M, Chatzigeorgiou A. The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis. Hepatology. 2020;71(1):363-374. https://doi.org/10.1002/hep.30834
Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology.2023;77(4):1335-1347. https://doi.org/10.1097/HEP.0000000000000004
Le MH, Le DM, Baez TC, Wu Y, Ito T, Lee EY, Nguyen MH. Global incidence of non-alcoholic fatty liver disease: a systematic review and meta-analysis of 63 studies and 1,201,807 persons. Journal of Hepatology.2023;79(2);287-295. https://doi.org/10.1016/j.jhep.2023.03.040
Hunt NJ, Kang SW, Lockwood GP, et al. Hallmarks of Aging in the Liver. Computational and structural biotechnology journal. 2019;17:1151–1161. https://doi.org/10.1016/j.csbj.2019.07.021
He QJ, Li YF, Zhao LT, Lin CT, Yu CY, Wang D. Recent advances in age-related metabolic dysfunction-associated steatotic liver disease. World Journal of Gastroenterology. 2024;30(7):652-662. https://doi.org/10.3748/wjg.v30.i7.652
Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018 Jul;24(7):908-922. https://doi.org/10.1038/s41591-018-0104-9
Poliakova DO, Kramar SB. Age Changes Of The Liver. Act. Probl. of the Modern Med. 2023;23(1):194-198. https://doi.org/10.31718/2077–1096.23.1.194
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217. https://doi.org/10.1016/j.cell.2013.05.039
Allaire M, Gilgenkrantz H. The aged liver: beyond cellular senescence. Clin Res Hepatol Gastroenterol. 2020;44:6–11. https://doi.org/10.1016/j.clinre.2019.07.011
Pinto C, Ninfole E, Gaggiano L, Benedetti A, Marzioni M, Maroni M. Aging and the biological response to liver injury. Semin Liver Dis. 2020;40:225–32. https://doi.org/10.1055/s-0039-3402033
Zarandi PK, Ghiasi M, Heiat M. The role and function of lncRNA in ageing-associated liver diseases. RNA biology.2025; 22(1):1-8. https://doi.org/10.1080/15476286.2024.2440678
Lettieri-Barbato D, Aquilano K, Punziano C, Minopoli G, Faraonio R. (2022). MicroRNAs, long non-coding RNAs, and circular RNAs in the redox control of cell senescence. Antioxidants.2022;11(3): 480. https://doi.org/10.3390/antiox11030480
Barbosa MC, Grosso RA, Fader MC. Hallmarks of aging: an autophagic perspective. Front Endocrinol. 2018;9:790. https://doi.org/10.3389/fendo.2018.00790
Schmucker DL.Age-related changes in liver structure and function: Implications for disease ?. Experimental gerontology. 2005;40(8-9):650–659. https://doi.org/10.1016/j.exger.2005.06.009
Conde de la Rosa L, Goicoechea L, Torres S, Garcia-Ruiz C, Fernandez-Checa JC. Role of oxidative stress in liver disorders. Livers. 2022; 2(4):283-314. https://doi.org/10.3390/livers2040023
Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev. 2020;34(23-24):1565-1576. https://doi.org/10.1101/gad.343129.120
Ribeiro-Rodrigues TM, Kelly G, Korolchuk VI, Girao H. Intercellular communication and aging. Aging.2023; 257-274. https://doi.org/10.1016/B978-0-12-823761-8.00005-7
Donahue EK, Ruark EM, Burkewitz K. Fundamental roles for inter-organelle communication in aging. Biochemical Society Transactions.2022;50(5):1389-1402. https://doi.org/10.1042/BST20220519
Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, Li J. Aging of Liver in Its Different Diseases. International Journal of Molecular Sciences. 2022;23(21):13085. https://doi.org/10.3390/ijms232113085
Zhang J, Lu T, Xiao J, Du C, Chen H, Li R, Zheng J. MSC-derived extracellular vesicles as nanotherapeutics for promoting aged liver regeneration. Journal of Controlled Release.2023;356:402-415. https://doi.org/10.1016/j.jconrel.2023.02.032
de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019;381:2541–2551. https://doi.org/10.1056/NEJMra1905136
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;10:146–154. https://doi.org/10.1007/s13668-021-00353-5
Anton SD, Moehl K, Donahoo WT, et al. Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting. Obesity. 2018;26:254–268. https://doi.org/10.1002/oby.22065
Malinowski B, Zalewska K, Węsierska A, et al. Intermittent Fasting in Cardiovascular Disorders-An Overview. Nutrients. 2019;11(3):673. https://doi.org/10.3390/nu11030673
Hourizadeh J, Munshi R, Zeltser R, Makaryus AN. Dietary Effects of Fasting on the Lipid Panel. Curr Cardiol Rev. 2024;20(2):82-92. https://doi.org/10.2174/011573403X257173231222042846
Gabel K, Varady KA. Current research: effect of time restricted eating on weight and cardiometabolic health. J Physiol. 2022;600(6):1313-1326. https://doi.org/10.1113/JP280542
Lange M, Nadkarni D, Martin L, Newberry C, Kumar S, Kushner T. Intermittent fasting improves hepatic end points in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Hepatol Commun. 2023 Aug 3;7(8):e0212. https://doi.org/10.1097/HC9.0000000000000212
Vasim I, Majeed CN, DeBoer MD. Intermittent Fasting and Metabolic Health. Nutrients. 2022 Jan 31;14(3):631. https://doi.org/10.3390/nu14030631
Kim KH, Lee MS. Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches. Front Endocrinol (Lausanne). 2018;9:485. https://doi.org/10.3389/fendo.2018.00485
Różański G, Pheby D, Newton JL, Murovska M, Zalewski P, Słomko J. Effect of different types of intermittent fasting on biochemical and anthropometric parameters among patients with metabolic-associated fatty liver disease (MAFLD)-A systematic review. Nutrients. 2021 Dec 26;14(1):91. https://doi.org/10.3390/nu14010091.
Gao Y, Tsintzas K, Macdonald IA, Cordon SM, Taylor MA. Effects of intermittent (5:2) or continuous energy restriction on basal and postprandial metabolism: A randomised study in normal-weight, young participants. Eur J Clin Nutr. 2022;76:65–73. https://doi.org/10.1038/s41430-021-00909-2
Wong VW, Wong GL, Chan RS, et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol. 2018;69(6):1349-1356. https://doi.org/10.1016/j.jhep.2018.08.011
Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, et al. Autophagy regulates lipid metabolism. Nature. 2009;458:1131‐1135. https://doi.org/10.1038/nature07976
Filali-Mouncef Y, Hunter C, Roccio F, Zagkou S, Dupont N, et al. The ménage à trois of autophagy, lipid droplets and liver disease. Autophagy. 2022 Jan;18(1):50-72. https://doi.org/10.1080/15548627.2021.1895658
Li D, Dun Y, Qi D, et al. Intermittent fasting activates macrophage migration inhibitory factor and alleviates high-fat diet-induced nonalcoholic fatty liver disease. Sci Rep. 2023 Aug 11;13(1):13068. URL: https://www.sciencedirect.com/science/article/pii/S2213231720308405?via%3Dihub
Deleyto-Seldas N, Efeyan A. The mTOR-Autophagy Axis and the Control of Metabolism. Front Cell Dev Biol. 2021 Jul 1;9:655731. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC8281972/
Strong R, Miller RA, Bogue M, et al. Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects. Aging Cell. 2020;19(11):e13269. https://doi.org/10.1111/acel.13269 URL: https://pubmed.ncbi.nlm.nih.gov/33145977/
Baghdadi M, Nespital T, Monzó C, Deelen J, Grönke S, Partridge L. Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension. Molecular metabolism. 2024;81:101902. https://doi.org/10.1016/j.molmet.2024.101902
Schreiber KH, Arriola Apelo SI, Yu D, et al. A novel rapamycin analog is highly selective for mTORC1 in vivo. Nat Commun. 2019;10(1):3194. https://doi.org/10.1038/s41467-019-11174-0 URL: https://pubmed.ncbi.nlm.nih.gov/31324799/
Nazeer B, Khawar MB, Khalid MU, Hamid SE, Rafiq M, Abbasi MH, Ahmad S. Emerging role of lipophagy in liver disorders. Molecular and Cellular Biochemistry.2024;479(1):1-11. https://doi.org/10.1007/s11010-023-04707-1
Conte M, Franceschi C, Sandri M, Salvioli S. Perilipin 2 and Age-Related Metabolic Diseases: A New Perspective. Trends Endocrinol Metab. 2016;27(12):893-903. https://doi.org/10.1016/j.tem.2016.09.001
Dalen KT, Ulven SM, Arntsen BM, Solaas K, Nebb HI. PPARalpha activators and fasting induce the expression of adipose differentiation-related protein in liver. J Lipid Res. 2006;47(5):931-943. https://doi.org/10.1194/jlr.M500459-JLR200
Zubiete-Franco I, García-Rodríguez JL, Martínez-Uña M, et al. Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis. J Hepatol. 2016;64(2):409-418. https://doi.org/10.1016/j.jhep.2015.08.037
Wood JG, Schwer B, Wickremesinghe PC, et al. Sirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster. Proc Natl Acad Sci USA. 2018;115(7):1564-1569. https://doi.org/10.1073/pnas.1720673115
Yuan Y, Cruzat VF, Newsholme P, Cheng J, Chen Y, Lu Y. Regulation of SIRT1 in aging: Roles in mitochondrial function and biogenesis. Mech Ageing Dev. 2016;155:10-21. https://doi.org/10.1016/j.mad.2016.02.003
Hammer SS, Vieira CP, McFarland D, et al. Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction. Diabetologia. 2021;64(7):1674-1689. https://doi.org/10.1007/s00125-021-05431-5
Yoshida M, Satoh A, Lin JB, et al. Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice. Cell Metab. 2019;30(2):329-342.e5. https://doi.org/10.1016/j.cmet.2019.05.015
Rambold AS, Cohen S, Lippincott-Schwartz J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev Cell. 2015;32(6):678-692. https://doi.org/10.1016/j.devcel.2015.01.029.
Zehmer JK, Huang Y, Peng G, et al. A role for lipid droplets in inter-membrane lipid traffic. Proteomics. 2009;9(4):914–921. https://doi.org/10.1002/pmic.200800584
Martinez-Lopez N, Garcia-Macia M, Sahu S, et al. Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver. Cell Metab. 2016;23(1):113-127. https://doi.org/10.1016/j.cmet.2015.10.008
Cingolani F, Czaja MJ. Regulation and Functions of Autophagic Lipolysis. Trends Endocrinol Metab. 2016;27(10):696-705. https://doi.org/10.1016/j.tem.2016.06.003
Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309-314. https://doi.org/10.1038/nature14893
Khaminets A, Heinrich T, Mari M, et al. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature. 2015;522(7556):354-358. https://doi.org/10.1038/nature14498
Mochida K, Nakatogawa H. ER-phagy: selective autophagy of the endoplasmic reticulum. EMBO Rep. 2022;23(8):e55192. https://doi.org/10.15252/embr.202255192 URL: https://pubmed.ncbi.nlm.nih.gov/35758175/
Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases. EMBO J. 2021;40(19):e108863. https://doi.org/10.15252/embj.2021108863 URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC8488577/
López-Otín C, Kroemer G. Hallmarks of Health Cell. Cell. 2021;184(1):33-63. https://doi.org/10.1016/j.cell.2020.11.034
Chung HY, Kim DH, Lee EK, et al. Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept. Aging Dis. 2019 Apr 1;10(2):367-382. https://doi.org/10.14336/AD.2018.0324
Shaw, A., Goldstein, D. & Montgomery, R. Age-dependent dysregulation of innate immunity. Nat Rev Immunol. 2013;13:875–887. https://doi.org/10.1038/nri3547
Arai Y, Martin-Ruiz CM, Takayama M, et al. Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians. E Bio Medicine. 2015 Jul 29;2(10):1549-58. https://doi.org/10.1016/j.ebiom.2015.07.029
Shen Y, Malik SA, Amir M, et al. Decreased Hepatocyte Autophagy Leads to Synergistic IL-1β and TNF Mouse Liver Injury and Inflammation. Hepatology. 2020 Aug;72(2):595-608. https://doi.org/10.1002/hep.31209
Ren LP, Chan SMH, Zeng XY, Laybutt DR, Iseli TJ, Sun RQ, et al. Differing Endoplasmic Reticulum Stress Response to Excess Lipogenesis versus Lipid Oversupply in Relation to Hepatic Steatosis and Insulin Resistance. PLoS ONE. 2012;7(2):e30816. https://doi.org/10.1371/journal.pone.0030816
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 Apr;18(2):162-72. https://doi.org/10.1089/rej.2014.1624
Allahverdi H. Exploring the therapeutic potential of plasma from intermittent fasting and untreated rats on aging-induced liver damage. J Cell Mol Med. 2024 Jun;28(12):e18456. https://doi.org/10.1111/jcmm.18456. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC11199341/#abstract1
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;2012(3):CD007176. https://doi.org/10.1002/14651858.CD007176.pub2
van der Rijt S, Molenaars M, McIntyre RL, Janssens GE, Houtkooper RH. Integrating the Hallmarks of Aging Throughout the Tree of Life: A Focus on Mitochondrial Dysfunction. Front Cell Dev Biol. 2020 Nov 26;8:594416. https://doi.org/10.3389/fcell.2020.594416
Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017;37:371-393. https://doi.org/10.1146/annurev-nutr-071816-064634
Uffelmann E, Huang QQ, Munung NS. et al. Genome-wide association studies. Nat Rev Methods Primers. 2021;1(59). https://doi.org/10.1038/s43586-021-00056-9
Huang DQ, Wilson LA, Behling C, et al. Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study. Gastroenterology. 2023;165(2):463-472.e5. https://doi.org/10.1053/j.gastro.2023.04.025
Sanyal AJ, Van Natta ML, Clark J, et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N Engl J Med. 2021;385(17):1559-1569. https://doi.org/10.1056/NEJMoa2029349
Rojas-Morales P, Pedraza-Chaverri J, Tapia E. Ketone bodies, stress response, and redox homeostasis. Redox Biol. 2020;29:101395. https://doi.org/10.1016/j.redox.2019.101395
Tajima T, Yoshifuji A, Matsui A, et al. β-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects. Kidney Int. 2019;95:1120–1137. https://doi.org/10.1016/j.kint.2018.11.034
Raja GR, Sadeesh KR. Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease. Front Physiol. 2022 July 04;3. https://doi.org/10.3389/fphys.2022.946474
Cotter DG, Ercal B, Huang X, Leid JM, d’Avignon DA, Graham MJ, et al. (2014). Ketogenesis Prevents Diet-Induced Fatty Liver Injury and Hyperglycemia. J. Clin. Invest. 2014;124:5175–5190. https://doi.org/10.1172/jci76388
Holmer M, Lindqvist C, Petersson S, et al. Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial. JHEP Rep. 2021;3(3):100256. https://doi.org/10.1016/j.jhepr.2021.100256
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