https://doi.org/10.4081/ejtm.2025.14214
Irisin and exercise activate renal anti-aging pathways and enhance survival in young mice: a translational insight into muscle-kidney crosstalk
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 2 December 2025
Irisin, a myokine released by skeletal muscle during physical activity, has emerged as a key regulator of energy metabolism, cellular stress responses, and longevity pathways. While previous studies have focused on aged animal-models or pathological states, the long-term impact of early-life interventions on molecular aging pathways remains poorly understood. This study investigated whether early-life irisin administration and physical exercise could modulate the renal-expression of Klotho and HSP70—two hallmark genes of cellular protection and anti-aging in young adult NMRI mice. Animals underwent 8 weeks of resistance training, endurance training, or irisin injection. Plasma irisin was quantified via ELISA, and renal Klotho and HSP70 expression levels were assessed using qPCR and Western-blotting. All interventions significantly increased circulating irisin and upregulated Klotho and HSP70 at both transcriptional and protein levels, with resistance training inducing the most pronounced effects. A 20-month survival analysis showed a trend toward improved longevity in all intervention groups. These findings suggest that early-life exercise and irisin exposure may activate renoprotective and longevity-associated pathways before the onset of molecular aging, supporting their potential as preventive strategies in translational geroscience.
Downloads
1. Tenchov R, Sasso JM, Wang X, Zhou QA. Aging hallmarks and progression and age-related diseases: a landscape view of research advancement. ACS Chem Neurosci 2023;15:1-30. DOI: https://doi.org/10.1021/acschemneuro.3c00531
2. López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013;153:1194-217. DOI: https://doi.org/10.1016/j.cell.2013.05.039
3. 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. DOI: https://doi.org/10.1038/s41392-022-01251-0
4. Xu Y, Sun Z. Molecular basis of Klotho: from gene to function in aging. Endocr Rev 2015;36:174-93. DOI: https://doi.org/10.1210/er.2013-1079
5. Kuro-o M. The Klotho proteins in health and disease. Nat Rev Nephrol 2019;15:27-44. DOI: https://doi.org/10.1038/s41581-018-0078-3
6. Prud’homme GJ, Kurt M, Wang Q. Pathobiology of the klotho antiaging protein and therapeutic considerations. Front Aging 2022;3:931331. DOI: https://doi.org/10.3389/fragi.2022.931331
7. Avin KG, Coen PM, Huang W, et al. Skeletal muscle as a regulator of the longevity protein, Klotho. Front Physiol 2014;5:189. DOI: https://doi.org/10.3389/fphys.2014.00189
8. Iturriaga Ramírez T, Yvert TP, Sánchez Lorente IM, et al. Acute Impacts of different types of exercise on circulating α-klotho protein levels. Front Physiol 2021;12:716473. DOI: https://doi.org/10.3389/fphys.2021.716473
9. Jiang S, Bae J-H, Wang Y, Song W. The potential roles of myokines in adipose tissue metabolism with exercise and cold exposure. Int J Molecular Sci 2022;23:11523. DOI: https://doi.org/10.3390/ijms231911523
10. Momenzadeh S, Zamani S, Dehghan F, et al. Comparative proteome analyses highlight several exercise‐like responses of mouse sciatic nerve after IP injection of irisin. Eur J Neurosci 2021;53:3262-77. DOI: https://doi.org/10.1111/ejn.15202
11. Gouda A, Tolba S, Mahrose K, et al. Heat shock proteins as a key defense mechanism in poultry production under heat stress conditions. Poultry Sci 2024:103537. DOI: https://doi.org/10.1016/j.psj.2024.103537
12. Dehghan F, Zamani S, Barreiro C, Jami MS. Irisin injection mimics exercise effects on the brain proteome. Eur J Neurosci 2021;54:7422-41. DOI: https://doi.org/10.1111/ejn.15493
13. Shahabi S, Esfarjani F, Reisi J, et alS. The effects of 8-week resistance and endurance trainings on bone strength compared to irisin injection protocol in mice. Adv Biomed Res 2021;10:40. DOI: https://doi.org/10.4103/abr.abr_220_20
14. De Sousa Lages A, Lopes V, Horta J, et al. Therapeutics that can potentially replicate or augment the anti-aging effects of physical exercise. Int J Molecular Sc 2022;23:9957. DOI: https://doi.org/10.3390/ijms23179957
15. Zhou S, Hum J, Taskintuna K, et al. The anti-aging hormone klotho promotes retinal pigment epithelium cell viability and metabolism by activating the AMPK/PGC-1α pathway. Antioxidants 2023;12:385. DOI: https://doi.org/10.3390/antiox12020385
16. Ji N, Luan J, Hu F, et al. Aerobic exercise‑stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney. Exper Ther Med 2018;16:3511-7. DOI: https://doi.org/10.3892/etm.2018.6597
17. Ghadamyari N, Zolfaghari MR, Tolouei Azar J, Fattahi A. The effect of 8 weeks of endurance and resistance exercises on the serum levels of FGF23 and s-Klotho in type 2 diabetic women. Int J Diabetes Dev Ctries 2025;45:472-9. DOI: https://doi.org/10.1007/s13410-024-01343-3
18. Shamsi MM, Mahdavi M, Quinn L, et al. Effect of resistance exercise training on expression of Hsp70 and inflammatory cytokines in skeletal muscle and adipose tissue of STZ-induced diabetic rats. Cell Stress Chaperones 2016;21:783-91. DOI: https://doi.org/10.1007/s12192-016-0703-7
19. Chen J, Zhou R, Feng Y, Cheng L. Molecular mechanisms of exercise contributing to tissue regeneration. Signal Transduct Target Ther 2022;7:383. DOI: https://doi.org/10.1038/s41392-022-01233-2
20. Lin J, Liu X, Zhou Y, et al. Molecular basis of irisin regulating the effects of exercise on insulin resistance. Applied Sci 2022;12:5837. DOI: https://doi.org/10.3390/app12125837
21. Laurens C, Bergouignan A, Moro C. Exercise-released myokines in the control of energy metabolism. Front Physiol 2020;11:91. DOI: https://doi.org/10.3389/fphys.2020.00091
22. Zhang H, Wu X, Liang J, et al. Irisin, an exercise-induced bioactive peptide beneficial for health promotion during aging process. Ageing Res Rev 2022;80:101680. DOI: https://doi.org/10.1016/j.arr.2022.101680
23. Zhang Y, Wang L, Kang H, et al. Unlocking the therapeutic potential of irisin: Harnessing its function in degenerative disorders and tissue regeneration. Int J Molecular Sci 2023;24:6551. DOI: https://doi.org/10.3390/ijms24076551
24. Rabiee F, Lachinani L, Ghaedi S, et al. New insights into the cellular activities of Fndc5/Irisin and its signaling pathways. Cell Biosci 2020;10:1-10. DOI: https://doi.org/10.1186/s13578-020-00413-3
25. Waseem R, Shamsi A, Mohammad T, et al. FNDC5/irisin: physiology and pathophysiology. Molecules 2022;27:1118. DOI: https://doi.org/10.3390/molecules27031118
26. Cui Y, Yu L, Cong W, et al. Irisin preserves mitochondrial integrity and function in tubular epithelial cells after ischemia–reperfusion‐induced acute kidney injury. Acta Physiol 2024;240:e14211. DOI: https://doi.org/10.1111/apha.14211
27. Sugiura H, Yoshida T, Mitobe M, et al. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70. Nephrol Dial Transplant 2010;25:60-8. DOI: https://doi.org/10.1093/ndt/gfp451
28. Rizk FH, Soliman NA, Heabah NA, et al. Fenofibrate improves cognitive impairment induced by high-fat high-fructose diet: a possible role of Irisin and heat shock proteins. ACS Chem Neurosci 2022;13:1782-9. DOI: https://doi.org/10.1021/acschemneuro.2c00186
29. Feng M, Li M, Lou J, et al. Early-life exercise extends healthspan but not lifespan in mice. Nat Commun 2025;16:6328. DOI: https://doi.org/10.1038/s41467-025-61443-4
30. Sahu A, Mamiya H, Shinde S, et al. Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nat Commun 2018;9:4859. DOI: https://doi.org/10.1038/s41467-018-07253-3
31. Prud’homme GJ, Wang Q. Anti-inflammatory role of the klotho protein and relevance to aging. Cells 2024;13:1413. DOI: https://doi.org/10.3390/cells13171413
32. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829-33. DOI: https://doi.org/10.1126/science.1112766
33. Li-Zhen L, Chen Z-c, Wang S-S, et al. Klotho deficiency causes cardiac ageing by impairing autophagic and activating apoptotic activity. Eur J Pharmacol 2021;911:174559. DOI: https://doi.org/10.1016/j.ejphar.2021.174559
CRediT authorship contribution
Zahra Sadat Aghili, conceptualization, methodology, investigation, data curation, writing – original draft; Mansour Homayoun, methodology, investigation, formal analysis; Hossein Rezazadeh, validation, resources, writing – review & editing; Saeed Zamani, conceptualization, methodology, supervision, project administration, funding acquisition. All authors read and approved the final manuscript.
How to Cite
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.