A new frontier in anti-aging: hepatic klotho and molecular targets

Abstract

Aging is a complex biological process characterized by the progressive accumulation of molecular and cellular damage, leading to a decline in homeostatic capacity and increased susceptibility to disease. The liver plays a central role in systemic aging due to its key functions in metabolism, detoxification, and immune regulation. Liver aging is driven by interconnected mechanisms inclu-ding cellular senescence, chronic low-grade inflammation (inflammaging), and mitochondrial dys-function, all of which contribute to a decline in hepatic function. Senescent hepatocytes secrete pro-inflammatory factors that enter systemic circulation and promote multi-organ aging. In recent years, the klotho protein family has emerged as a critical regulator of aging. Circulating α-Klotho exerts anti-inflammatory, antioxidant, and anti-fibrotic effects, whereas β-Klotho plays a pivotal role in hepatic metabolic regulation through FGF19 and FGF21 signaling pathways. Klotho has been shown to modulate key signaling pathways associated with aging, including TGF-β, NF-κB, IGF-1, and Wnt/β-catenin, thereby attenuating age-related pathological processes. This review provides a comprehensive overview of the role of the liver in aging and the mechanistic effects of klotho pro-teins, highlighting their potential as therapeutic targets in liver aging and associated metabolic disorders.

Keywords

• Liver
• Klotho Proteins
• Aging
• Inflammation

Yaşlanma karşıtı yeni bir ufuk: karaciğerde klotho ve moleküler hedefler

Abstract

Yaşlanma, moleküler ve hücresel düzeyde biriken hasarın organizmanın homeostatik kapasitesini azaltmasıyla karakterize karmaşık bir süreçtir. Bu süreçte karaciğer, metabolizma, detoksifikasyon ve immün yanıtın düzenlenmesindeki merkezi rolü nedeniyle sistemik yaşlanmanın önemli bir belirleyicisi olarak öne çıkmaktadır. Karaciğer yaşlanması; hücresel yaşlanma kronik inflamasyon ve mitokondriyal disfonksiyon gibi birbiriyle ilişkili mekanizmalar aracılığıyla gelişmekte ve or-ganın fonksiyonel kapasitesinde azalmaya yol açmaktadır. Yaşlanmış hücrelerin salgıladığı pro-inflamatuvar faktörler sistemik dolaşıma katılarak çoklu organ yaşlanmasını hızlandırmaktadır. Son yıllarda klotho protein ailesi, yaşlanma biyolojisinde önemli bir düzenleyici olarak dikkat çekmek-tedir. α-Klotho’nun dolaşımdaki formu anti-inflamatuvar, antioksidan ve anti-fibrotik etkiler göste-rirken; β-Klotho karaciğerde FGF19 ve FGF21 aracılığıyla metabolik homeostazın düzenlenmesin-de kritik rol oynamaktadır. Klothonun TGF-β, NF-κB, IGF-1 ve Wnt/β-katenin gibi temel sinyal yolaklarını düzenleyerek yaşlanma ile ilişkili süreçleri baskıladığı gösterilmiştir. Bu derlemede, karaciğerin yaşlanma sürecindeki rolü ve klotho proteinlerinin bu süreçteki etkileri güncel literatür ışığında ele alınmış; klothonun karaciğer yaşlanması ve ilişkili metabolik hastalıklarda potansiyel bir terapötik hedef olabileceği vurgulanmıştır.

Keywords

• Karaciğer
• Klotho Proteinleri
• Yaşlanma
• İnflamasyon

References

1. 1. Guo J, Huang X, Dou L, et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther 2022;7:391. https://doi.org/10.1038/s41392-022-01251-0.
2. 2. López-Otín C, Blasco MA, Partridge L, et al. Hallmarks of aging: An expanding universe. Cell 2023;186:243–78. https://doi.org/10.1016/j.cell.2022.11.001.
3. 3. Hunt NJ, Kang SW (Sophie), Lockwood GP, et al. Hallmarks of Aging in the Liver. Comput Struct Bio-technol J 2019;17:1151–61. https://doi.org/10.1016/j.csbj.2019.07.021.
4. 4. Prattichizzo F, Frigé C, Pellegrini V, et al. Organ-specific biological clocks: Ageotyping for personalized anti-aging medicine. Ageing Res Rev 2024;96:102253. https://doi.org/10.1016/j.arr.2024.102253.
5. 5. Lu Y, Brommer B, Tian X, et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 2020;588:124–9. https://doi.org/10.1038/s41586-020-2975-4.
6. 6. Schaum N, Lehallier B, Hahn O, et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature 2020;583:596–602. https://doi.org/10.1038/s41586-020-2499-y.
7. 7. Tian YE, Cropley V, Maier AB, et al. Heteroge-neous aging across multiple organ systems and prediction of chronic disease and mortality. Nat Med 2023;29:1221–31. https://doi.org/10.1038/s41591-023-02296-6.
8. 8. Radonjić T, Dukić M, Jovanović I, et al. Aging of Liver in Its Different Diseases. Int J Mol Sci 2022;23:13085. https://doi.org/10.3390/ijms232113085.

9. 9. Kiourtis C, Terradas-Terradas M, Gee LM, et al. Hepatocellular senescence induces multi-organ senescen-ce and dysfunction via TGFβ. Nat Cell Biol 2024;26:2075–83. https://doi.org/10.1038/s41556-024-01543-3.
10. 10. Zhong L, Wang L, Syed JN, et al. Liver aging: underlying mechanisms and therapeutic strategies. Mol Aspects Med 2025;105:101397. https://doi.org/10.1016/j.mam.2025.101397.
11. 11. Kale A, Sankrityayan H, Anders H-J, et al. Klotho in kidney diseases: a crosstalk between the renin-angiotensin system and endoplasmic reticulum stress 2021. https://doi.org/10.1093/ndt/gfab340.
12. 12. Kuro-o M, Matsumura Y, Aizawa H, et al. Muta-tion of the mouse klotho gene leads to a syndrome re-sembling ageing. Nature 1997 390:6655 1997;390:45–51. https://doi.org/10.1038/36285.
13. 13. Matsumura Y, Aizawa H, Shiraki-Iida T, et al. Identification of the HumanKlothoGene and Its Two Transcripts Encoding Membrane and SecretedKlothoPro-tein. Biochem Biophys Res Commun 1998;242:626–30. https://doi.org/10.1006/BBRC.1997.8019.
14. 14. Hajare AD, Dagar N, Bhanudas Gaikwad A. REVIEW Open Access Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases n.d. https://doi.org/10.1186/s43556-025-00253-y.
15. 15. Di Micco R, Krizhanovsky V, Baker D, et al. Cellular senescence in ageing: from mechanisms to thera-peutic opportunities. Nat Rev Mol Cell Biol 2021;22:75–95. https://doi.org/10.1038/s41580-020-00314-w.
16. 16. Mohamad Kamal NS, Safuan S, Shamsuddin S, et al. Aging of the cells: Insight into cellular senescence and detection Methods. Eur J Cell Biol 2020;99:151108. https://doi.org/10.1016/j.ejcb.2020.151108.
17. 17. Childs BG, Baker DJ, Kirkland JL, et al. Senes-cence and apoptosis: dueling or complementary cell fates? EMBO Rep 2014;15:1139–53. https://doi.org/10.15252/embr.201439245.
18. 18. Teissier T, Boulanger E, Cox LS. Interconnecti-ons between Inflammageing and Immunosenescence during Ageing. Cells 2022;11:359. https://doi.org/10.3390/cells11030359.
19. 19. Chung HY, Kim DH, Lee EK, et al. Redefining Chronic Inflammation in Aging and Age-Related Disea-ses: Proposal of the Senoinflammation Concept. Aging Dis 2019;10:367. https://doi.org/10.14336/AD.2018.0324.
20. 20. Li X, Li C, Zhang W, et al. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther 2023;8:239. https://doi.org/10.1038/s41392-023-01502-8.
21. 21. Teissier T, Boulanger E, Cox LS. Interconnecti-ons between Inflammageing and Immunosenescence during Ageing. Cells 2022;11:359. https://doi.org/10.3390/cells11030359.
22. 22. Nousis L, Kanavaros P, Barbouti A. Oxidative Stress-Induced Cellular Senescence: Is Labile Iron the Connecting Link? Antioxidants 2023;12:1250. https://doi.org/10.3390/antiox12061250.
23. 23. Chaudhary MR, Chaudhary S, Sharma Y, et al. Aging, oxidative stress and degenerative diseases: mec-hanisms, complications and emerging therapeutic strate-gies. Biogerontology 2023;24:609–62. https://doi.org/10.1007/s10522-023-10050-1.
24. 24. Xu X, Pang Y, Fan X. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances. Signal Transduct Target Ther 2025;10:190. https://doi.org/10.1038/s41392-025-02253-4.
25. 25. Ganguly S, Sakane S, Hokutan K, et al. Aging and Aging-Related Senescence in Liver. Semin Liver Dis 2025;45:549–66. https://doi.org/10.1055/a-2637-2549.
26. 26. Zhang X, Gao Y, zhang S, et al. Mitochondrial dysfunction in the regulation of aging and aging-related diseases. Cell Communication and Signaling 2025;23:290. https://doi.org/10.1186/s12964-025-02308-7.
27. 27. Henry J, Ahad M. The etymology of liver in ancient Greek and Latin. J Hepatol 2025;82:171–3. https://doi.org/10.1016/j.jhep.2024.09.042.
28. 28. Gan C, Yuan Y, Shen H, et al. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025;10:33. https://doi.org/10.1038/s41392-024-02072-z.
29. 29. Schmucker DL. Age-related changes in liver structure and function: Implications for disease ? Exp Gerontol 2005;40:650–9. https://doi.org/10.1016/j.exger.2005.06.009.
30. 30. Yao Y-Q, Cao Q-Y, Li Z. Delaying liver aging: Analysis of structural and functional alterations. World J Gastroenterol 2025;31. https://doi.org/10.3748/wjg.v31.i15.103773.
31. 31. Williams SN, Ding W-X. The impact of aging on liver health and the development of liver diseases. Hepa-tol Commun 2025;9. https://doi.org/10.1097/HC9.0000000000000808.
32. 32. Xu Y, Deng Q, Chen Y, et al. Liver aging and associated diseases. Chinese Science Bulletin 2026;71:1369–78. https://doi.org/10.1360/CSB-2025-5918.
33. 33. Wong VW-S, Ekstedt M, Wong GL-H, et al. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol 2023;79:842–52. https://doi.org/10.1016/j.jhep.2023.04.036.
34. 34. Chen C, Wang L. Aging and metabolic dysfunc-tion-associated steatotic liver disease: a bidirectional relationship. Front Med 2025;19:427–38. https://doi.org/10.1007/s11684-025-1133-7.
35. 35. Friedman SL, Neuschwander-Tetri BA, Rinella M, et al. Mechanisms of NAFLD development and thera-peutic strategies. Nat Med 2018;24:908–22. https://doi.org/10.1038/s41591-018-0104-9.
36. 36. Li Q, Xiao N, Zhang H, et al. Systemic aging and aging‐related diseases. The FASEB Journal 2025;39. https://doi.org/10.1096/fj.202402479RRR.
37. 37. Ogrodnik M, Evans SA, Fielder E, et al. Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice. Aging Cell 2021;20. https://doi.org/10.1111/acel.13296.
38. 38. Almalki WH, Almujri SS. Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis. Biogerontology 2025;26:10. https://doi.org/10.1007/s10522-024-10153-3.
39. 39. Wei P, Zhang X, Yan C, et al. Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies. Biogerontology 2025;26:142. https://doi.org/10.1007/s10522-025-10273-4.
40. 40. Prud’homme GJ, Wang Q. Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging. Cells 2024;13:1413. https://doi.org/10.3390/CELLS13171413.
41. 41. Dalton GD, Xie J, An S-W, et al. New Insights into the Mechanism of Action of Soluble Klotho. Front Endocrinol (Lausanne) 2017;8. https://doi.org/10.3389/fendo.2017.00323.
42. 42. Zhong X, Jagarlapudi S, Weng Y, et al. Structure-function relationships of the soluble form of the antia-ging protein Klotho have therapeutic implications for managing kidney disease. Journal of Biological Che-mistry 2020;295:3115–33. https://doi.org/10.1074/jbc.RA119.012144.
43. 43. Kuro-o M. Klotho and calciprotein particles as therapeutic targets against accelerated ageing. Clin Sci 2021;135:1915–27. https://doi.org/10.1042/CS20201453.
44. 44. Aaldijk AS, Verzijl CRC, Jonker JW, et al. Bio-logical and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho. Front Endocrinol (Lau-sanne) 2023;14. https://doi.org/10.3389/fendo.2023.1150222.
45. 45. Yuan Q, Ren Q, Li L, et al. A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling. Nat Commun 2022;13. https://doi.org/10.1038/S41467-022-28096-Z.
46. 46. Hori S, Miyake M, Tatsumi Y, et al. Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer. Oncotarget 2018;9:19508–24. https://doi.org/10.18632/oncotarget.24628.
47. 47. Chen L, Liu H, Liu J, et al. Klotho Endows Hepatoma Cells with Resistance to Anoikis via VEGFR2/PAK1 Activation in Hepatocellular Carcino-ma. PLoS One 2013;8:e58413. https://doi.org/10.1371/journal.pone.0058413.
48. 48. Marwein M, Mukhim L, Sah P, et al. Klotho in aging and diseases: molecular features, expressions, and functional implications. Mol Cell Biochem 2025;481:739–56. https://doi.org/10.1007/s11010-025-05445-2.
49. 49. Shiraki-Iida T, Iida A, Nabeshima Y, et al. Imp-rovement of multiple pathophysiological phenotypes of klotho (kl/kl) mice by adenovirus-mediated expression of the klotho gene. J Gene Med 2000;2:233–42. https://doi.org/10.1002/1521-2254(200007/08)2:4<233::AID-JGM110>3.0.CO;2-5.
50. 50. Prud’homme GJ, Kurt M, Wang Q. Pathobiology of the Klotho Antiaging Protein and Therapeutic Consi-derations. Frontiers in Aging 2022;3. https://doi.org/10.3389/fragi.2022.931331.
51. 51. Kurosu H, Ogawa Y, Miyoshi M, et al. Regula-tion of Fibroblast Growth Factor-23 Signaling by Klotho. Journal of Biological Chemistry 2006;281:6120–3. https://doi.org/10.1074/jbc.C500457200.
52. 52. Kurosu H, Yamamoto M, Clark JD, et al. Supp-ression of Aging in Mice by the Hormone Klotho. Scien-ce (1979) 2005;309:1829–33. https://doi.org/10.1126/science.1112766.
53. 53. Lorenzi O, Veyrat-Durebex C, Wollheim CB, et al. Evidence against a direct role of klotho in insulin resistance. Pflugers Arch 2010;459:465–73. https://doi.org/10.1007/s00424-009-0735-2.
54. 54. Zeng Y, Wang P-H, Zhang M, et al. Aging-related renal injury and inflammation are associated with down-regulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice. Aging Clin Exp Res 2016;28:69–76. https://doi.org/10.1007/s40520-015-0371-y.
55. 55. Buchanan S, Combet E, Stenvinkel P, et al. Klotho, Aging, and the Failing Kidney. Front Endocrinol (Lausanne) 2020;11. https://doi.org/10.3389/fendo.2020.00560.
56. 56. Ohsawsa Y, Nishimatsu S, Saito F, et al. 267P Circulating alpha-Klotho combats TGF-beta-induced sarcopenia. Neuromuscular Disorders 2024;43:104441.76. https://doi.org/10.1016/j.nmd.2024.07.085.
57. 57. Miao J, Huang J, Luo C, et al. Klotho retards renal fibrosis through targeting mitochondrial dysfunc-tion and cellular senescence in renal tubular cells. Phy-siol Rep 2021;9. https://doi.org/10.14814/phy2.14696.
58. 58. Zhou L, Li Y, Zhou D, et al. Loss of Klotho Contributes to Kidney Injury by Derepression of Wnt/β-Catenin Signaling. Journal of the American Society of Nephrology 2013;24:771–85. https://doi.org/10.1681/ASN.2012080865.
59. 59. Sun H, Gao Y, Lu K, et al. Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. World J Surg Oncol 2015;13:307. https://doi.org/10.1186/s12957-015-0717-0.
60. 60. Rao Z, Landry T, Li P, et al. Administration of alpha klotho reduces liver and adipose lipid accumula-tion in obese mice. Heliyon 2019;5:e01494. https://doi.org/10.1016/j.heliyon.2019.e01494.
61. 61. Rao Z, Landry T, Li P, et al. Administration of alpha klotho reduces liver and adipose lipid accumula-tion in obese mice. Heliyon 2019;5:e01494. https://doi.org/10.1016/j.heliyon.2019.e01494.
62. 62. Gu H, Jiang W, You N, et al. Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes. Mol Ther Methods Clin Dev 2020;18:811–23. https://doi.org/10.1016/j.omtm.2020.08.002.
63. 63. Liu Y, Chen M. Emerging role of α-Klotho in energy metabolism and cardiometabolic diseases. Diabe-tes & Metabolic Syndrome: Clinical Research & Reviews 2023;17:102854. https://doi.org/10.1016/j.dsx.2023.102854.
64. 64. Landry T, Shookster D, Huang H. Circulating α-klotho regulates metabolism via distinct central and peripheral mechanisms. Metabolism 2021;121:154819. https://doi.org/10.1016/j.metabol.2021.154819.
65. 65. Tan H, Huang W, Luo H, et al. Klotho-derived peptide 1 ameliorates hepatic fibrosis induced by αKlotho deficiency and liver injury. Int J Biol Sci 2026;22:1425–39. https://doi.org/10.7150/ijbs.122107.
66. 66. Aaldijk AS, Struik D, Driessen S, et al. Beta-Klotho Protein Expression in Healthy Human Tissues and Liver Biopsies From Patients With MASLD or MASH. Gastro Hep Advances 2025;4:100745. https://doi.org/10.1016/j.gastha.2025.100745.
67. 67. Meroni M, Dongiovanni P, Tiano F, et al. β-Klotho as novel therapeutic target in Metabolic Dysfunc-tion-Associated Steatotic Liver Disease (MASLD): A narrative review. Biomedicine & Pharmacotherapy 2024;180:117608. https://doi.org/10.1016/j.biopha.2024.117608.
68. 68. Lin BC, Wang M, Blackmore C, et al. Liver-specific Activities of FGF19 Require Klotho beta. Jour-nal of Biological Chemistry 2007;282:27277–84. https://doi.org/10.1074/jbc.M704244200.
69. 69. Dongiovanni P, Crudele A, Panera N, et al. β-Klotho gene variation is associated with liver damage in children with NAFLD. J Hepatol 2020;72:411–9. https://doi.org/10.1016/j.jhep.2019.10.011.
70. 70. Ji F, Liu Y, Hao J-G, et al. KLB gene polymorp-hism is associated with obesity and non-alcoholic fatty liver disease in the Han Chinese. Aging 2019;11:7847–58. https://doi.org/10.18632/aging.102293.
71. 71. Wu F, Pan J, Chen M, et al. Association of serum klotho with cognitive function among individuals with nonalcoholic fatty liver disease. Front Aging Neurosci 2024;16. https://doi.org/10.3389/fnagi.2024.1487182.
72. 72. Chi Z, Teng Y, Liu Y, et al. Association between klotho and non-alcoholic fatty liver disease and liver fibrosis based on the NHANES 2007–2016. Ann Hepa-tol 2023;28:101125. https://doi.org/10.1016/j.aohep.2023.101125.
73. 73. Hou Z, Ding Q, Li Y, et al. Intestinal epithelial β Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury. EBioMe-dicine 2022;82:104181. https://doi.org/10.1016/j.ebiom.2022.104181.
74. 74. Zhou D, Shi Y, Zhang D, et al. Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis. Redox Biol 2024;76:103333. https://doi.org/10.1016/j.redox.2024.103333.
75. 75. Liu Z, Wei S, Jiang Y, et al. Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepa-titis via the mTORC1 pathway. J Hepatol 2025;83:630–42. https://doi.org/10.1016/j.jhep.2025.02.003.
76. 76. Du K, Umbaugh DS, Dutta RK, et al. A systemic effect for liver senescence. Nat Cell Biol 2024;26:2016–7. https://doi.org/10.1038/s41556-024-01520-w.
77. 77. Shahmoon S, Rubinfeld H, Wolf I, et al. The aging suppressor klotho: a potential regulator of growth hormone secretion. American Journal of Physiology-Endocrinology and Metabolism 2014;307:E326–34. https://doi.org/10.1152/ajpendo.00090.2014.