Exercise-Induced Mitochondrial Stress and cGAS-STING Signaling in Healthy Aging

Öz

Purpose: This review aims to examine the potential relationship between exercise-induced mitochondrial adaptation, mitochondrial DNA (mtDNA) homeostasis, and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling during brain aging. Particular emphasis is placed on the role of mitochondrial quality control and the proposed mitochondrial stress-resolution threshold as a potential mechanism linking exercise with healthy brain aging and longevity.

Method: A focused narrative review was conducted by evaluating human, animal, and in vitro/cellular studies, together with relevant review articles, addressing exercise-induced mitochondrial adaptation, mitochondrial quality control, mtDNA homeostasis, cGAS-STING signaling, neuroinflammation, and brain aging. Evidence from different biological levels was narratively synthesized to examine the potential mechanistic relationship between exercise-induced mitochondrial stress and age-related innate immune activation.

Results: Exercise-induced mitochondrial stress can promote mitochondrial biogenesis, turnover, antioxidant defense, and mitochondrial resilience. Aging may impair these adaptive processes and increase mitochondrial dysfunction and mtDNA dysregulation. Cytosolic mtDNA can activate cGAS-STING signaling, while emerging evidence links this pathway to microglial activation and neuroinflammation during brain aging. However, direct evidence connecting exercise with modulation of the brain mtDNA-cGAS-STING axis remains limited.

Conclusion: Exercise may influence age-related neuroinflammation primarily by improving mitochondrial quality control and maintaining mtDNA homeostasis rather than through direct suppression of cGAS-STING signaling. The proposed mitochondrial stress-resolution threshold provides a testable framework linking exercise dose, mitochondrial adaptation, mtDNA regulation, innate immune signaling, and healthy brain aging.

Anahtar Kelimeler

• Exercise
• Aging
• Mitochondrial Dysfunction
• Mitochondrial DNA
• cGAS-STING
• Neuroinflammation

Sağlıklı Yaşlanmada Egzersize Bağlı Mitokondriyal Stres ve cGAS-STING Sinyalizasyonu

Öz

Amaç: Bu derlemenin amacı, egzersize bağlı mitokondriyal adaptasyon, mitokondriyal DNA (mtDNA) homeostazı ve beyin yaşlanması sırasında siklik GMP-AMP sentaz–interferon genlerinin (cGAS-STING) uyarıcısı sinyal yolakları arasındaki potansiyel ilişkiyi incelemektir. Özellikle, mitokondriyal kalite kontrolünün ve önerilen mitokondriyal stres-çözülme eşiğinin egzersiz ile sağlıklı beyin yaşlanması ve uzun yaşam arasındaki potansiyel mekanizmadaki rolü ele alınmıştır.

Yöntem: Egzersize bağlı mitokondriyal adaptasyon, mitokondriyal kalite kontrolü, mtDNA homeostazı, cGAS-STING sinyalizasyonu, nöroinflamasyon ve beyin yaşlanmasını ele alan insan, hayvan ve in vitro/hücresel çalışmalar ile ilgili derleme makaleleri değerlendirilerek odaklanmış bir derleme gerçekleştirilmiştir. Farklı biyolojik düzeylerden elde edilen kanıtlar, egzersize bağlı mitokondriyal stres ile yaşa bağlı doğuştan bağışıklık aktivasyonu arasındaki potansiyel mekanistik ilişkiyi incelemek amacıyla sentezlenmiştir.

Bulgular: Egzersize bağlı mitokondriyal stres; mitokondriyal biyogenez, mitokondriyal dönüşüm, antioksidan savunma ve mitokondriyal dayanıklılığı destekleyebilir. Yaşlanma bu adaptif süreçleri bozarak mitokondriyal disfonksiyon ve mtDNA düzensizliğini artırabilir. Sitozolik mtDNA, cGAS-STING sinyal yolunu aktive edebilirken, gelişmekte olan kanıtlar bu yolun beyin yaşlanması sırasında mikroglial aktivasyon ve nöroinflamasyon ile ilişkili olduğunu göstermektedir. Bununla birlikte, egzersizin beyindeki mtDNA-cGAS-STING eksenini modüle ettiğini doğrudan gösteren kanıtlar halen sınırlıdır.

Sonuç: Egzersiz, cGAS-STING sinyalizasyonunu doğrudan baskılamaktan ziyade mitokondriyal kalite kontrolünü iyileştirerek ve mtDNA homeostazını koruyarak yaşlanmaya bağlı nöroinflamasyonu etkileyebilir. Önerilen mitokondriyal stres-çözülme eşiği modeli; egzersiz dozu, mitokondriyal adaptasyon, mtDNA düzenlenmesi, doğuştan bağışıklık sinyalizasyonu ve sağlıklı beyin yaşlanması arasındaki ilişkiyi açıklamak için test edilebilir bir çerçeve sunmaktadır.

Anahtar Kelimeler

• Egzersiz
• Yaşlanma
• Mitokondriyal Disfonksiyon
• Mitokondriyal DNA
• cGAS-STING
• Nöroinflamasyon

Kaynakça

1. Abrego-Guandique, D. M., Aguilera Rojas, N. M., Chiari, A., Luciani, F., Cione, E., & Cannataro, R. (2025). The impact of exercise on mitochondrial biogenesis in skeletal muscle: A systematic review and meta-analysis of randomized trials. Biomolecular Concepts, 16(1). https://doi.org/10.1515/BMC-2025-0055
2. Algieri, C., Nesci, S., & Oppedisano, F. (2025). Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance. Journal of Translational Medicine 2025 23:1, 23(1), 1321-. https://doi.org/10.1186/S12967-025-07392-4
3. Alizadeh Pahlavani, H., Laher, I., Knechtle, B., & Zouhal, H. (2022). Exercise and mitochondrial mechanisms in patients with sarcopenia. Frontiers in Physiology, 13. https://doi.org/10.3389/FPHYS.2022.1040381
4. Bartman, S., Coppotelli, G., & Ross, J. M. (2024). Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases. Current Issues in Molecular Biology 2024, Vol. 46, Pages 1987-2026, 46(3), 1987–2026. https://doi.org/10.3390/CIMB46030130
5. Bondy, S. C. (2024). Mitochondrial Dysfunction as the Major Basis of Brain Aging. Biomolecules 2024, Vol. 14, Page 402, 14(4), 402. https://doi.org/10.3390/BIOM14040402
6. Botella, J., Perri, E., Caruana, N. J., López-Calcerrada, S., Brischigliaro, M., Jamnick, N. A., … Bishop, D. J. (2025). Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men. Nature Communications, 17(1). https://doi.org/10.1038/S41467-025-66625-8
7. Broome, S. C., Whitfield, J., Karagounis, L. G., & Hawley, J. A. (2024). Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing. Sports Medicine 2024 54:9, 54(9), 2291–2309. https://doi.org/10.1007/S40279-024-02072-7
8. Burtscher, J., Millet, G. P., Place, N., Kayser, B., & Zanou, N. (2021). The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection. International Journal of Molecular Sciences, 22(12), 6479. https://doi.org/10.3390/IJMS22126479

9. Burtscher, J., Soltany, A., Visavadiya, N. P., Burtscher, M., Millet, G. P., Khoramipour, K., & Khamoui, A. V. (2023). Mitochondrial stress and mitokines in aging. Aging Cell, 22(2), e13770. https://doi.org/10.1111/ACEL.13770;WGROUP:STRING:PUBLICATION
10. Cai, T., Li, Y., Zhang, Y., Li, C., Li, S., & Zhang, Q. (2026). The role of exercise-mediated mitochondrial quality control remodeling in aging. Frontiers in Cell and Developmental Biology, 14, 1792645. https://doi.org/10.3389/FCELL.2026.1792645/FULL
11. Campos, J. C., Bozi, L. H. M., Krum, B., Bechara, L. R. G., Ferreira, N. D., Arini, G. S., … Ferreira, J. C. B. (2023). Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics. Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2204750120. https://doi.org/10.1073/PNAS.2204750120;SUBPAGE:STRING:FULL
12. Cardinale, D. A., Gejl, K. D., Petersen, K. G., Nielsen, J., Ortenblad, N., & Larsen, F. J. (2021). Short-term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes. Journal of Applied Physiology (Bethesda, Md. : 1985), 131(1), 388–400. https://doi.org/10.1152/JAPPLPHYSIOL.00829.2020
13. Choi, J. W., Jo, S. W., Kim, D. E., Paik, I. Y., & Balakrishnan, R. (2024). Aerobic exercise attenuates LPS-induced cognitive dysfunction by reducing oxidative stress, glial activation, and neuroinflammation. Redox Biology, 71. https://doi.org/10.1016/j.redox.2024.103101
14. Chrøis, K. M., Dohlmann, T. L., Søgaard, D., Hansen, C. V., Dela, F., Helge, J. W., & Larsen, S. (2020). Mitochondrial adaptations to high intensity interval training in older females and males. European Journal of Sport Science, 20(1), 135–145. https://doi.org/10.1080/17461391.2019.1615556
15. Decout, A., Katz, J. D., Venkatraman, S., & Ablasser, A. (2021). The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nature Reviews Immunology 2021 21:9, 21(9), 548–569. https://doi.org/10.1038/s41577-021-00524-z
16. El Assar, M., Álvarez-Bustos, A., Sosa, P., Angulo, J., & Rodríguez-Mañas, L. (2022). Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging. International Journal of Molecular Sciences, 23(15). https://doi.org/10.3390/IJMS23158713
17. Feng, Z. T., Zhang, Y. Y., & Xue, C. X. (2026). Bioactive compounds and exercise in aging and neurodegeneration: mechanistic insights from the gut–brain–metabolic axis. Frontiers in Nutrition, 13, 1781176. https://doi.org/10.3389/FNUT.2026.1781176/TEXT
18. Flensted-Jensen, M., Weinreich, C. M., Kleis-Olsen, A. S., Hansen, F., Skyggelund, N. S., Pii, J. R., … Dela, F. (2026). Resistance-based training improves mitochondrial capacity and redox balance in aging adults, independent of polyphenol supplementation. Redox Biology, 89, 103972. https://doi.org/10.1016/J.REDOX.2025.103972
19. Gorgori-Gonzalez, A., Soto-Rodriguez, S., Tamayo-Torres, E., Garcia-Dominguez, E., Sebastia, V., Gambini, J., … Gomez-Cabrera, M. C. (2026). Leveraging mitochondrial stress to improve healthy aging. Sports Medicine and Health Science, 8(1), 23–33. https://doi.org/10.1016/J.SMHS.2025.10.003
20. Guilbaud, E., Sarosiek, K. A., & Galluzzi, L. (2024). Inflammation and mitophagy are mitochondrial checkpoints to aging. Nature Communications, 15(1). https://doi.org/10.1038/S41467-024-47840-1
21. Gusdon, A. M., Callio, J., Distefano, G., O’Doherty, R. M., Goodpaster, B. H., Coen, P. M., & Chu, C. T. (2017). Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Experimental Gerontology, 90, 1–13. https://doi.org/10.1016/J.EXGER.2017.01.013
22. Izquierdo, J. M. (2024). Mitochondria–cGAS–STING axis is a potential therapeutic target for senescence-dependent inflammaging-associated neurodegeneration. Neural Regeneration Research, 20(3), 805. https://doi.org/10.4103/NRR.NRR-D-24-00245
23. Jiménez-Loygorri, J. I., Villarejo-Zori, B., Viedma-Poyatos, Á., Zapata-Muñoz, J., Benítez-Fernández, R., Frutos-Lisón, M. D., … Boya, P. (2024). Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging. Nature Communications 2024 15:1, 15(1), 830-. https://doi.org/10.1038/s41467-024-45044-1
24. Jurcau, M. C., Jurcau, A., Cristian, A., Hogea, V. O., Diaconu, R. G., & Nunkoo, V. S. (2024). Inflammaging and Brain Aging. International Journal of Molecular Sciences 2024, Vol. 25, Page 10535, 25(19), 10535. https://doi.org/10.3390/IJMS251910535
25. Karagianni, C., & Bazopoulou, D. (2024). Redox regulation in lifespan determination. Journal of Biological Chemistry, 300(3), 105761. https://doi.org/10.1016/J.JBC.2024.105761
26. Kim, J., Kim, H. S., & Chung, J. H. (2023). Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway. Experimental & Molecular Medicine, 55(3), 510–519. https://doi.org/10.1038/S12276-023-00965-7
27. Klemmensen, M. M., Borrowman, S. H., Pearce, C., Pyles, B., & Chandra, B. (2024). Mitochondrial dysfunction in neurodegenerative disorders. Neurotherapeutics, 21(1), e00292. https://doi.org/10.1016/J.NEUROT.2023.10.002
28. Kong, J., Xie, Y., Fan, R., Wang, Q., Luo, Y., & Dong, P. (2025). Exercise orchestrates systemic metabolic and neuroimmune homeostasis via the brain–muscle–liver axis to slow down aging and neurodegeneration: a narrative review. European Journal of Medical Research 2025 30:1, 30(1), 475-. https://doi.org/10.1186/S40001-025-02751-9
29. Konopka, A. R., Suer, M. K., Wolff, C. A., & Harber, M. P. (2014). Markers of human skeletal muscle mitochondrial biogenesis and quality control: Effects of age and aerobic exercise training. The Journals of Gerontology: Series A, 69(4), 371–378. https://doi.org/10.1093/gerona/glt107
30. Li, H., Cai, R., Zhou, Y., Jiang, Y., & Tan, S. (2025). cGAS-STING signaling in brain aging and neurodegeneration: molecular links and therapeutic perspectives. Journal of Neuroinflammation 2025 22:1, 22(1), 235-. https://doi.org/10.1186/S12974-025-03563-8
31. Li, K., Wang, L., Zhu, D., Wang, W., Guo, Y., Gao, H., … Xiao, W. (2026). β-Hydroxybutyrate Acts as an Exercise Mimetic to Protect the Aging Liver. Aging Cell, 25(1). https://doi.org/10.1111/ACEL.70314
32. Li, Y., Cui, J., Liu, L., Hambright, W. S., Gan, Y., Zhang, Y., … Mu, X. (2024). mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells. Cell Death & Disease 2024 15:7, 15(7), 523-. https://doi.org/10.1038/s41419-024-06863-8
33. Li, Y., Mallika, A. P., Baghel, M. S., Shravage, B. V., & Shang, P. (2026). Editorial: Mitochondrial dysfunction in cellular and molecular mechanisms of brain aging. Frontiers in Aging Neuroscience, 18, 1866752. https://doi.org/10.3389/FNAGI.2026.1866752/TEXT
34. Liang, J., Wang, C., Zhang, H., Huang, J., Xie, J., & Chen, N. (2021). Exercise-Induced Benefits for Alzheimer’s Disease by Stimulating Mitophagy and Improving Mitochondrial Function. Frontiers in Aging Neuroscience, 13. https://doi.org/10.3389/FNAGI.2021.755665
35. Lim, A. Y., Chen, Y. C., Hsu, C. C., Fu, T. C., & Wang, J. S. (2022). The Effects of Exercise Training on Mitochondrial Function in Cardiovascular Diseases: A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences 2022, Vol. 23, Page 12559, 23(20), 12559. https://doi.org/10.3390/IJMS232012559
36. Lippi, L., de Sire, A., Mezian, K., Curci, C., Perrero, L., Turco, A., … Invernizzi, M. (2022). Impact of exercise training on muscle mitochondria modifications in older adults: a systematic review of randomized controlled trials. Aging Clinical and Experimental Research 2022 34:7, 34(7), 1495–1510. https://doi.org/10.1007/S40520-021-02073-W
37. Luo, L., Dai, J. R., Guo, S. S., Lu, A. M., Gao, X. F., Gu, Y. R., … Qin, Z. H. (2017). Lysosomal Proteolysis Is Associated With Exercise-Induced Improvement of Mitochondrial Quality Control in Aged Hippocampus. The Journals of Gerontology: Series A, 72(10), 1342–1351. https://doi.org/10.1093/GERONA/GLW242
38. Ma, G., Wang, E., Yan, X., Xu, X. X., Li, X., Ma, X., … Xie, X. (2026). Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS–STING. Neuroscience Bulletin 2026, 1–19. https://doi.org/10.1007/S12264-026-01657-8
39. Ma, J., Son, A. Y., Son, Y., Wang, P. yuan, & Hwang, P. M. (2026). Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise. Trends in Endocrinology and Metabolism, 37(2), 115–123. https://doi.org/10.1016/j.tem.2025.05.004
40. Ma, Y., Song, R., & Duan, C. (2025). Mitochondrial quality control and transfer communication in neurological disorders and neuroinflammation. Frontiers in Immunology, 16, 1542369. https://doi.org/10.3389/FIMMU.2025.1542369/FULL
41. Maciel, P., Lamas, C. B., Araújo, A. C., Chagas, E. F. B., Guiguer, E. L., Curi, R., … Barbalho, S. M. (2026). Physical Exercise Counteracts Impaired Cognition by Improving Mitochondrial Function. International Journal of Molecular Sciences 2026, Vol. 27, Page 4337, 27(10), 4337. https://doi.org/10.3390/IJMS27104337
42. Maldonado, E., Morales-Pison, S., Urbina, F., & Solari, A. (2023). Aging Hallmarks and the Role of Oxidative Stress. Antioxidants 2023, Vol. 12, Page 651, 12(3), 651. https://doi.org/10.3390/ANTIOX12030651
43. Mănescu, D. C., Tudor, A., Mănescu, A. M., Mărgărit, I. R., Mănescu, C. O., Prisăcaru, C., … Tudor, V. (2026). Antioxidants and Exercise: A Redox-Informed Framework for Training Adaptation, Performance, and Recovery. Antioxidants, 15(4), 456. https://doi.org/10.3390/ANTIOX15040456/S1
44. Mee-Inta, O., Zhao, Z. W., & Kuo, Y. M. (2019). Physical Exercise Inhibits Inflammation and Microglial Activation. Cells, 8(7). https://doi.org/10.3390/CELLS8070691
45. Mela, V., Mota, B. C., Milner, M., McGinley, A., Mills, K. H. G., Kelly, Á. M., & Lynch, M. A. (2020). Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells. Brain, Behavior, and Immunity, 87, 413–428. https://doi.org/10.1016/j.bbi.2020.01.012
46. Menshikova, E. V., Ritov, V. B., Fairfull, L., Ferrell, R. E., Kelley, D. E., & Goodpaster, B. H. (2006). Effects of Exercise on Mitochondrial Content and Function in Aging Human Skeletal Muscle. The Journals of Gerontology: Series A, 61(6), 534–540. https://doi.org/10.1093/GERONA/61.6.534
47. Mesquita, P. H. C., Osburn, S. C., Godwin, J. S., Roberts, M. D., & Kavazis, A. N. (2022). Effects of aging and long-term physical activity on mitochondrial physiology and redox state of the cortex and cerebellum of female rats. Physiological Reports, 10(24), e15542. https://doi.org/10.14814/PHY2.15542;JOURNAL:JOURNAL:2051817X;WEBSITE:WEBSITE:PHYSOC;ISSUE:ISSUE:DOI
48. Militello, R., Luti, S., Gamberi, T., Pellegrino, A., Modesti, A., & Modesti, P. A. (2024). Physical Activity and Oxidative Stress in Aging. Antioxidants (Basel, Switzerland), 13(5). https://doi.org/10.3390/ANTIOX13050557
49. Mølmen, K. S., Almquist, N. W., & Skattebo, Ø. (2025). Effects of Exercise Training on Mitochondrial and Capillary Growth in Human Skeletal Muscle: A Systematic Review and Meta-Regression. Sports Medicine (Auckland, N.Z.), 55(1), 115–144. https://doi.org/10.1007/S40279-024-02120-2
50. Newman, L. E., & Shadel, G. S. (2023). Mitochondrial DNA Release in Innate Immune Signaling. Annual Review of Biochemistry, 92(Volume 92, 2023), 299–332. https://doi.org/10.1146/ANNUREV-BIOCHEM-032620-104401/CITE/REFWORKS
51. Özdemir, K., & Demir, Y. (2025). Phenolic Compounds in Exercise Physiology: Dual Role in Oxidative Stress and Recovery Adaptation. Food Science & Nutrition, 13(8), e70714. https://doi.org/10.1002/FSN3.70714
52. Picca, A., Faitg, J., Auwerx, J., Ferrucci, L., & D’Amico, D. (2023). Mitophagy in human health, ageing and disease. Nature Metabolism 2023 5:12, 5(12), 2047–2061. https://doi.org/10.1038/s42255-023-00930-8
53. Pradeepkiran, J. A., Islam, M. A., Sehar, U., Reddy, A. P., Vijayan, M., & Reddy, P. H. (2025). Impact of diet and exercise on mitochondrial quality and mitophagy in Alzheimer’s disease. Ageing Research Reviews, 108, 102734. https://doi.org/10.1016/J.ARR.2025.102734
54. Quan, S., Fu, X., Cai, H., Ren, Z., Xu, Y., & Jia, L. (2025). The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease. Molecular Neurodegeneration, 20(1). https://doi.org/10.1186/S13024-025-00815-2
55. Rim, C., You, M. J., Nahm, M., & Kwon, M. S. (2024). Emerging role of senescent microglia in brain aging-related neurodegenerative diseases. Translational Neurodegeneration 2024 13:1, 13(1), 10-. https://doi.org/10.1186/S40035-024-00402-3
56. Rongvaux, A., Jackson, R., Harman, C. C. D., Li, T., West, A. P., De Zoete, M. R., … Flavell, R. A. (2014). Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA. Cell, 159(7), 1563–1577. https://doi.org/10.1016/j.cell.2014.11.037
57. Salminen, A., Kaarniranta, K., & Kauppinen, A. (2025). Activation of cGAS-STING signaling in senescent cells promotes the aging process by remodeling the functions of the immune system. Biogerontology, 27(1). https://doi.org/10.1007/S10522-025-10353-5
58. Slavin, M. B., Memme, J. M., Oliveira, A. N., Moradi, N., & Hood, D. A. (2022). Regulatory networks coordinating mitochondrial quality control in skeletal muscle. Https://Doi.Org/10.1152/Ajpcell.00065.2022, 322(5), C913–C926. https://doi.org/10.1152/AJPCELL.00065.2022
59. Steffan, D., Pezzini, C., Esposito, M., & Franco-Romero, A. (2025). Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease. Biomolecules 2025, Vol. 15, Page 1252, 15(9), 1252. https://doi.org/10.3390/BIOM15091252
60. Suk, K. (2026). Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration. Experimental Neurology, 401, 115737. https://doi.org/10.1016/J.EXPNEUROL.2026.115737
61. Szechyńska-Hebda, M., Ghalami, R. Z., Kamran, M., Van Breusegem, F., & Karpiński, S. (2022). To Be or Not to Be? Are Reactive Oxygen Species, Antioxidants, and Stress Signalling Universal Determinants of Life or Death? Cells 2022, Vol. 11, Page 4105, 11(24), 4105. https://doi.org/10.3390/CELLS11244105
62. Taskin, S., Celik, H., Demiryurek, S., Turedi, S., & Taskin, A. (2022). Effects of different-intensity exercise and creatine supplementation on mitochondrial biogenesis and redox status in mice. Iranian Journal of Basic Medical Sciences, 25(8), 1009–1015. https://doi.org/10.22038/IJBMS.2022.65047.14321
63. Tigano, M., Vargas, D. C., Tremblay-Belzile, S., Fu, Y., & Sfeir, A. (2021). Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature, 591(7850), 477–481. https://doi.org/10.1038/S41586-021-03269-W
64. Turkel, I., Kubat, G. B., Fatsa, T., Acet, O., Ozerklig, B., Yazgan, B., … Kosar, S. N. (2025). Acute treadmill exercise induces mitochondrial unfolded protein response in skeletal muscle of male rats. Biochimica et Biophysica Acta - Bioenergetics, 1866(2). https://doi.org/10.1016/j.bbabio.2024.149532
65. Wang, Y., Li, J., Zhang, Z., Wang, R., Bo, H., & Zhang, Y. (2023). Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle. Life, 13(4), 1006. https://doi.org/10.3390/LIFE13041006
66. Wei, P., Zhang, X., Yan, C., Sun, S., Chen, Z., & Lin, F. (2025). Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies. Biogerontology, 26(4). https://doi.org/10.1007/S10522-025-10273-4
67. Wen, X., Yang, F., Zhang, L., & Huang, D. (2026). Mitochondrial DNA as a driver of inflammation via the cGAS-STING pathway. Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.], 75(1). https://doi.org/10.1007/S00011-026-02231-8
68. West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., … Shadel, G. S. (2015). Mitochondrial DNA stress primes the antiviral innate immune response. Nature, 520(7548), 553–557. https://doi.org/10.1038/NATURE14156
69. White, M. J., McArthur, K., Metcalf, D., Lane, R. M., Cambier, J. C., Herold, M. J., … Kile, B. T. (2014). Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production. Cell, 159(7), 1549-1562. https://doi.org/10.1016/J.CELL.2014.11.036
70. Wu, Z., Jia, R. J., Zhang, Q., Huang, L. Y., Yan, J. T., Zhang, Y. H., & Fan, Y. G. (2026). The cGAS-STING pathway at the crossroads of neuroimmunology: bridging innate immunity to aging and neurodegeneration. Biomarker Research 2026 14:1, 14(1), 34-. https://doi.org/10.1186/S40364-026-00906-2
71. Wyckelsma, V. L., Levinger, I., McKenna, M. J., Formosa, L. E., Ryan, M. T., Petersen, A. C., Anderson, M. J., & Murphy, R. M. (2017). Preservation of skeletal muscle mitochondrial content in older adults: Relationship between mitochondria, fibre type and high-intensity exercise training. The Journal of Physiology, 595(11), 3345–3359. https://doi.org/10.1113/JP273950
72. Xu, X., Pang, Y., & Fan, X. (2025). Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances. Signal Transduction and Targeted Therapy 2025 10:1, 10(1), 190-. https://doi.org/10.1038/s41392-025-02253-4
73. Yun, H. R., Singh, M. K., Han, S., Ranbhise, J. S., Seo, H., Kim, S. S., & Kang, I. (2026). Skeletal Muscle Redox Signaling in Health and Disease: From Molecular Mechanisms to Therapeutic Exercise Strategies. Antioxidants 2026, Vol. 15, Page 678, 15(6), 678. https://doi.org/10.3390/ANTIOX15060678
74. Zhang, Z., & Zhang, C. (2025). Regulation of cGAS–STING signalling and its diversity of cellular outcomes. Nature Reviews Immunology 2025 25:6, 25(6), 425–444. https://doi.org/10.1038/s41577-024-01112-7
75. Zhou, Q., Luo, J., Chai, X., Yang, J., Zhong, S., Zhang, Z., … Wang, H. (2025). Therapeutic targeting the cGAS−STING pathway associated with protein and gene: An emerging and promising novel strategy for aging-related neurodegenerative disease. International Immunopharmacology, 156. https://doi.org/10.1016/j.intimp.2025.114679
76. Zhou, Z., Gao, J., Wang, M., & Zhang, H. (2026). Exercise-induced mitochondrial remodeling in energy-demanding organs during aging. IScience, 29(8), 116791. https://doi.org/10.1016/J.ISCI.2026.116791
77. Zhu, S., Zhang, L., Tong, P., Chen, J., Wang, C., Wang, Z., … Jiang, B. (2025). Nicotinamide Riboside Mitigates Retinal Degeneration by Suppressing Damaged DNA-Stimulated Microglial Activation and STING-Mediated Pyroptosis. Investigative Ophthalmology & Visual Science, 66(4), 14–14. https://doi.org/10.1167/IOVS.66.4.14
78. Zhu, X., Shi, L., Dong, Y., Sun, Y., & Jin, Q. (2026). Mechanisms by Which Exercise Delays Brain Aging Through Regulation of the Mitochondrial Quality Control System. Biology, 15(11), 854. https://doi.org/10.3390/BIOLOGY15110854