Klotho (a-Klotho MAB) / Follistatin (FLGR242)

Klotho Research

Research on α-Klotho spans multiple systems, revealing its role as both a membrane-bound coreceptor and a circulating protein with diverse enzymatic activities.

Mineral Metabolism and Bone-Kidney Interactions

Klotho functions as an obligate coreceptor for FGF23, creating a complex that regulates phosphate excretion by the kidneys[1]. The protein also modulates sodium-phosphate cotransporters in kidney tubules through its enzymatic activity, affecting how cells reabsorb or excrete phosphate[2].

Beyond the FGF23 pathway, Klotho influences vitamin D metabolism and parathyroid hormone secretion[3]. These mechanisms connect mineral balance across bone and kidney tissue.

Oxidative Stress and Cellular Defense

Klotho activates Nrf2, a master regulator of antioxidant gene expression. This activation increases production of protective enzymes including heme oxygenase-1 and glutathione-related enzymes[4].

The protein also works through FoxO transcription factors to regulate manganese superoxide dismutase expression. This coordination creates cellular responses that reduce reactive oxygen species accumulation in cardiac, lung, vascular, and kidney tissue[5].

Cardiovascular and Vascular Function

In cardiac cells, Klotho modulates calcium channels and ionic currents through PI3K/Akt signaling pathways[6]. The protein affects vascular smooth muscle cells by inducing antioxidant defenses that protect against vascular aging processes[7].

Klotho also influences nitric oxide signaling in endothelial cells and demonstrates protective effects against vascular calcification and fibrosis[8].

Neurological Function and Synaptic Activity

Research shows Klotho affects synaptic transmission and plasticity in hippocampal circuits[9]. In astrocytes, the protein enhances glycolytic metabolism, potentially supporting neuronal energy supply.

Klotho provides protection against neurotoxic insults through oxidative stress reduction and PI3K/Akt pathway regulation. The protein also modulates autophagy and endoplasmic reticulum stress responses in neuronal tissues[10].

Inflammatory Response Modulation

Klotho inhibits NF-κB, a key regulator of inflammatory gene expression, reducing production of inflammatory cytokines and chemokines[4]. The protein also affects MAPK pathways that transmit inflammation and stress signals[11].

In various injury models, Klotho reduces inflammatory cell infiltration and decreases pro-inflammatory molecule expression.

Glucose Metabolism and Insulin Signaling

Klotho’s relationship with insulin signaling involves context-dependent mechanisms[12]. In pancreatic beta cells, the protein enhances glucose-stimulated insulin secretion through calcium channel regulation[13].

In liver tissue, soluble Klotho improves glucose and lipid metabolism by modulating the IGF1R/PI3K/Akt/mTOR pathway[14]. The protein influences cell surface expression of TRPV2 channels, which facilitate calcium entry.

Skeletal Muscle and Regeneration

Klotho participates in muscle progenitor cell function and their progression through regenerative stages[15]. When Klotho levels decline, muscle progenitor cells exhibit mitochondrial DNA damage and reduced cellular energy production[16].

Research documents correlations between circulating Klotho levels and grip strength, suggesting connections between the protein and functional muscle capacity[17].

Wnt and TGF-β Signaling Pathways

Klotho functions as an antagonist of Wnt signaling by binding to Wnt ligands and blocking their interaction with cell surface receptors[18]. This inhibition affects cell proliferation, differentiation, and tissue development programs.

The protein also interacts with TGF-β signaling pathways, which regulate fibrosis, inflammation, and cellular senescence in various tissues[19].

FoxO Activation and Stress Resistance

Klotho activates FoxO transcription factors by inhibiting the PI3K/Akt pathway[20]. This allows FoxO proteins to translocate to the nucleus and induce expression of protective genes.

Target genes include those encoding antioxidant enzymes, DNA repair proteins, and autophagy regulators[21]. This signaling axis links Klotho to cellular stress responses and functional maintenance.

Mitochondrial Function and Energetics

Klotho influences mitochondrial biogenesis and the generation of new mitochondria[20]. In muscle progenitor cells, Klotho deficiency leads to mitochondrial DNA damage and impaired respiratory function[16].

The protein modulates expression of mitochondrial uncoupling proteins and regulators of mitochondrial dynamics, affecting cellular metabolic programs[22].

DNA Integrity and Genomic Protection

Research indicates Klotho preserves mitochondrial DNA integrity when cells face oxidative stress[10]. The protein reduces DNA double-strand breaks caused by various insults[23].

These protective effects involve Akt signaling and possible DNA repair pathway activation, connecting to broader roles in cellular senescence processes.

Ion Channel and Membrane Transport Regulation

Klotho functions as a glycosidase that removes sugar molecules from membrane proteins[24]. For the TRPV5 calcium channel, Klotho removes sialic acid residues from N-glycans, affecting channel trafficking and stability[25].

This modification prevents channel endocytosis, increasing surface expression and enhancing calcium reabsorption in kidney tubules[26].

Autophagy and Protein Quality Control

Klotho influences autophagic flux and interacts with endoplasmic reticulum stress pathways[9]. In neurons, the protein increases proteasome activity, clearing damaged proteins[10].

This coordination between Klotho and cellular clearance mechanisms may be particularly relevant in tissues where protein aggregation occurs.

Cell Survival and Apoptosis Regulation

Klotho modulates programmed cell death through effects on the PI3K/Akt pathway and downstream caspase enzymes[27]. The protein affects expression of pro-apoptotic and anti-apoptotic proteins[23].

In various cell types, Klotho protects against cytotoxic insults and reduces apoptosis induced by oxidative stress or inflammatory signals[11].

Anti-Fibrotic Properties

Klotho demonstrates anti-fibrotic properties by modulating TGF-β signaling, a major driver of fibrosis in kidney, liver, and lung tissue[28]. Through Wnt signaling effects, Klotho influences epithelial-to-mesenchymal transition[18].

The protein reduces expression of profibrotic genes and extracellular matrix proteins in various organ injury models[19].

Enzymatic Activities

Klotho possesses β-glucuronidase activity, capable of cleaving glucuronic acid residues from substrates[29]. The protein also functions as a sialidase, removing sialic acid from glycoproteins[30].

These enzymatic activities occur through specific catalytic sites in Klotho’s extracellular domain, allowing direct modification of membrane protein function[31].

References

1. M. S. Razzaque, “The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis,” Springer Science and Business Media LLC, Nov. 2009. doi: 10.1038/nrendo.2009.196. https://doi.org/10.1038/nrendo.2009.196
2. M. C. Hu et al., “Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule,” Wiley, May 2010. doi: 10.1096/fj.10-154765. https://doi.org/10.1096/fj.10-154765
3. M. C. Hu, K. Shiizaki, M. Kuro-o, and O. W. Moe, “Fibroblast Growth Factor 23 and Klotho: Physiology and Pathophysiology of an Endocrine Network of Mineral Metabolism,” Annual Reviews, Feb. 2013. doi: 10.1146/annurev-physiol-030212-183727. https://doi.org/10.1146/annurev-physiol-030212-183727
4. X. Zhao et al., “New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms,” Frontiers Media SA, Sep. 2024. doi: 10.3389/fimmu.2024.1454142. https://doi.org/10.3389/fimmu.2024.1454142
5. M. Yamamoto et al., “Regulation of Oxidative Stress by the Anti-aging Hormone Klotho*♦,” Elsevier BV, Nov. 2005. doi: 10.1074/jbc.m509039200. https://doi.org/10.1074/jbc.m509039200
6. Y. Hung et al., “Klotho modulates electrical activity and calcium homeostasis in pulmonary vein cardiomyocytes via PI3K/Akt signalling,” Oxford University Press (OUP), Jun. 2020. doi: 10.1093/europace/euaa100. https://doi.org/10.1093/europace/euaa100
7. G. Maltese et al., “The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells,” Wiley, Oct. 2016. doi: 10.1111/jcmm.12996. https://doi.org/10.1111/jcmm.12996
8. C. B. Leibrock et al., “NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency,” Ovid Technologies (Wolters Kluwer Health), Oct. 2015. doi: 10.1681/asn.2014030230. https://doi.org/10.1681/asn.2014030230
9. A. M. Orellana, C. H. Mazucanti, L. P. dos Anjos, L. de Sá Lima, E. M. Kawamoto, and C. Scavone, “Klotho increases antioxidant defenses in astrocytes and ubiquitin–proteasome activity in neurons,” Springer Science and Business Media LLC, Sep. 2023. doi: 10.1038/s41598-023-41166-6. https://doi.org/10.1038/s41598-023-41166-6
10. J. Mytych, “Klotho and neurons: mutual crosstalk between autophagy, endoplasmic reticulum, and inflammatory response,” Medknow, 2021. doi: 10.4103/1673-5374.303014. https://doi.org/10.4103/1673-5374.303014
11. A. Al-Kadi, A. Anter, R. R. Rofaeil, M. M. Sayed-Ahmed, and A.-S. F. Ahmed, “Klotho: A multifaceted protector in sepsis-induced organ damage and a potential therapeutic target,” Baishideng Publishing Group Inc., Sep. 2025. doi: 10.5492/wjccm.v14.i3.103458. https://doi.org/10.5492/wjccm.v14.i3.103458
12. T. Landry, D. Shookster, and H. Huang, “Circulating α-klotho regulates metabolism via distinct central and peripheral mechanisms,” Elsevier BV, Aug. 2021. doi: 10.1016/j.metabol.2021.154819. https://doi.org/10.1016/j.metabol.2021.154819
13. R. Anour, O. Andrukhova, E. Ritter, U. Zeitz, and R. G. Erben, “Klotho Lacks a Vitamin D Independent Physiological Role in Glucose Homeostasis, Bone Turnover, and Steady-State PTH Secretion In Vivo,” Public Library of Science (PLoS), Feb. 2012. doi: 10.1371/journal.pone.0031376. https://doi.org/10.1371/journal.pone.0031376
14. Y. Lin and Z. Sun, “Antiaging Gene Klotho Enhances Glucose-Induced Insulin Secretion by Up-Regulating Plasma Membrane Levels of TRPV2 in MIN6 β-Cells,” The Endocrine Society, May 2012. doi: 10.1210/en.2012-1091. https://doi.org/10.1210/en.2012-1091
15. Z. Clemens et al., “The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function,” eLife Sciences Publications, Ltd, Apr. 2021. doi: 10.7554/elife.61138. https://doi.org/10.7554/elife.61138
16. E. Arroyo, A. D. Troutman, R. N. Moorthi, K. G. Avin, A. R. Coggan, and K. Lim, “Klotho: An Emerging Factor With Ergogenic Potential,” Frontiers Media SA, Jan. 2022. doi: 10.3389/fresc.2021.807123. https://doi.org/10.3389/fresc.2021.807123
17. R. D. Semba et al., “Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study,” Springer Science and Business Media LLC, Jul. 2011. doi: 10.1007/s00421-011-2072-3. https://doi.org/10.1007/s00421-011-2072-3
18. A. Kale, H. Sankrityayan, H.-J. Anders, and A. B. Gaikwad, “Klotho in kidney diseases: a crosstalk between the renin–angiotensin system and endoplasmic reticulum stress,” Oxford University Press (OUP), Nov. 2021. doi: 10.1093/ndt/gfab340. https://doi.org/10.1093/ndt/gfab340
19. M. C. Hu, A. Bian, J. Neyra, and M. Zhan, “Klotho, stem cells, and aging,” Informa UK Limited, Aug. 2015. doi: 10.2147/cia.s84978. https://doi.org/10.2147/cia.s84978
20. J. Donate-Correa, B. Martín-Carro, J. B. Cannata-Andía, C. Mora-Fernández, and J. F. Navarro-González, “Klotho, Oxidative Stress, and Mitochondrial Damage in Kidney Disease,” MDPI AG, Jan. 2023. doi: 10.3390/antiox12020239. https://doi.org/10.3390/antiox12020239
21. X. Sun, W.-D. Chen, and Y.-D. Wang, “DAF-16/FOXO Transcription Factor in Aging and Longevity,” Frontiers Media SA, Aug. 2017. doi: 10.3389/fphar.2017.00548. https://doi.org/10.3389/fphar.2017.00548
22. A. Sahu et al., “Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration,” Springer Science and Business Media LLC, Nov. 2018. doi: 10.1038/s41467-018-07253-3. https://doi.org/10.1038/s41467-018-07253-3
23. S.-J. Kim et al., “Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis,” American Physiological Society, Jul. 2017. doi: 10.1152/ajplung.00063.2017. https://doi.org/10.1152/ajplung.00063.2017
24. S.-K. Cha, B. Ortega, H. Kurosu, K. P. Rosenblatt, M. Kuro-o, and C.-L. Huang, “Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1,” Proceedings of the National Academy of Sciences, Jul. 2008. doi: 10.1073/pnas.0803223105. https://doi.org/10.1073/pnas.0803223105
25. M. T. F. Wolf, S.-W. An, M. Nie, M. S. Bal, and C.-L. Huang, “Klotho Up-regulates Renal Calcium Channel Transient Receptor Potential Vanilloid 5 (TRPV5) by Intra- and Extracellular N-glycosylation-dependent Mechanisms,” Elsevier BV, Dec. 2014. doi: 10.1074/jbc.m114.616649. https://doi.org/10.1074/jbc.m114.616649
26. G. D. Dalton, J. Xie, S.-W. An, and C.-L. Huang, “New Insights into the Mechanism of Action of Soluble Klotho,” Frontiers Media SA, Nov. 2017. doi: 10.3389/fendo.2017.00323. https://doi.org/10.3389/fendo.2017.00323
27. P. Zhou, C. Zhao, Y. Chen, X. Liu, C. Wu, and Z. Hu, “Klotho activation of Nrf2 inhibits the ferroptosis signaling pathway to ameliorate sepsis-associated acute kidney injury,” AME Publishing Company, Dec. 2023. doi: 10.21037/tau-23-573. https://doi.org/10.21037/tau-23-573
28. A. D. Hajare, N. Dagar, and A. B. Gaikwad, “Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases,” Springer Science and Business Media LLC, Mar. 2025. doi: 10.1186/s43556-025-00253-y. https://doi.org/10.1186/s43556-025-00253-y
29. Y. Xu and Z. Sun, “Molecular Basis of Klotho: From Gene to Function in Aging,” The Endocrine Society, Feb. 2015. doi: 10.1210/er.2013-1079. https://doi.org/10.1210/er.2013-1079
30. O. Tohyama et al., “Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides.,” Journal of Biological Chemistry, vol. 279 11, pp. 9777–84, 2004.
31. E. S. Kuzina et al., “Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity,” Proceedings of the National Academy of Sciences, Apr. 2019. doi: 10.1073/pnas.1822055116. https://doi.org/10.1073/pnas.1822055116