The role of sirtuins on inflammation

Sirtuins, a family of seven regulatory enzymes (SIRT1-SIRT7), play a significant role in longevity, metabolism, antioxidant defense, and cell cycle regulation [1]. These enzymes, dependent on NAD+ (a cofactor) for their histone deacetylase activity, are found in body and have a protective role against DNA damage, cancer cell formation, and inflammation. Moreover, research studies reported their role in numerous biological functions, including cellular metabolism and genome stability [1]. Interestingly, their presence in vital organs such as liver and kidney help mitigation of stress and inflammatory reactions [2, 3].  

The ability of sirtuins to promote longevity is closely linked to their function in enhancing the body’s response to stress, regulating energy efficiency, and preventing cellular damage [1]. For example, nuclear sirtuins like SIRT1, SIRT6, and SIRT7 are involved in modifying histones and regulating gene expression, which determines the onset of cellular aging and provides cytoprotective activity [4, 5]. On the other hand, mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play roles in regulating oxidative stress directly within cells, thereby reducing reactive oxygen species that can lead to cellular damage and aging [1, 4, 5]. Furthermore, sirtuins’ involvement in neurodegeneration prevention and heart muscle cell protection highlights their importance in maintaining health and preventing age-related diseases. Their neuroprotective actions, through antioxidative and mitochondria-protective actions, and their role in cardiac ischemia show how sirtuins can mitigate conditions that often worsen with age, such as neurodegenerative diseases and heart problems [1, 4, 5].

Sirtuins against Inflammation

Sirtuins play a crucial role in protecting the body from inflammation and oxidative stress, two key contributors to numerous diseases. By modulating key transcription factors such as NF-κB and AP-1, sirtuins can significantly reduce the expression of pro-inflammatory cytokines, thereby suppressing inflammation [6, 7]. For example, SIRT1 directly inhibits NF-κB by deacetylating the p65 subunit, leading to decreased pro-inflammatory signals. Similarly, SIRT2’s activity can reduce inflammation by modifying NF-κB activity, and SIRT6 suppresses NF-κB signaling by deacetylating histones at NF-κB target gene promoters [6].

Sirtuins also help control inflammation by affecting inflammasomes. Studies showed that SIRT1 and SIRT2 manage the assembly and activation of the NLRP3 inflammasome, preventing excessive inflammation [6]. Additionally, SIRT1, SIRT3, and SIRT6 also act on AP-1, a factor that controls pro-inflammatory cytokines, showing their ability to reduce inflammation [6].

Besides, sirtuins modify antioxidant enzymes directly, enhancing the body’s ability to neutralize reactive oxygen species (ROS). SIRT2’s interaction with glucose-6-phosphate dehydrogenase (G6PD) and SIRT3’s modifications of superoxide dismutase 2 (SOD2) are examples of how sirtuins can enhance antioxidant defenses. Additionally, SIRT3’s ability to deacetylate and activate peroxiredoxin 3 (Prx3) highlights its role in protecting cells from oxidative damage [6].

Sirtuins against Tumor

Sirtuins, especially SIRT1, SIRT3, and SIRT6, play key roles in suppression of tumor growth, highlighting their importance in preventing and treating cancer. These proteins, by regulating cellular metabolism, inflammation, and DNA repair processes, contribute to the suppression of tumor growth and the promotion of genomic stability. SIRT1 affects many tumor-fighting pathways through its ability to remove acetyl groups from proteins. It blocks NF-κB signaling, which is crucial for lowering inflammation linked to cancer growth, by deacetylating NF-κB’s p65 unit [5, 6]. Moreover, SIRT1 also supports DNA repair and keeps the genome stable. It does this by activating SIRT6, which improves DNA repair and silences gene expression by removing acetyl groups from histones [5, 6]. This reduces the risk of mutations that might lead to cancer. Furthermore, SIRT1’s ability to activate MnSOD, Trx-1, and Bcl-xL, while inhibiting Bax protein, demonstrates its potential to reduce oxidative stress and apoptosis, which are common in tumor environments [5, 6].

Moreover, SIRT3 acts predominantly within mitochondria, protecting against oxidative stress and DNA damage, which can give rise to cancerous mutations. By deacetylating and activating enzymes like MnSOD, SIRT3 reduces ROS production, a key factor in DNA damage and subsequent tumor development. Moreover, SIRT3’s role in maintaining mitochondrial integrity and function indirectly supports cellular health and prevents carcinogenesis [5, 8].

Furthermore, SIRT6 acts directly on the genome to promote stability and repair, crucial in preventing carcinogenesis. Its ability to deacetylate histone H3 at Lys 56 facilitates DNA repair and conservation, thereby minimizing DNA damage accumulation, a primary driver of cancer. SIRT6 also inhibits HIF-1 alpha, a factor often overactivated in cancer cells to drive glucose metabolism under hypoxic conditions. By regulating HIF-1 alpha, SIRT3 prevents the metabolic reprogramming that supports tumor growth [5, 9]. Moreover, SIRT6’s actions in inhibiting c-Jun and rescuing p53 function further highlight its role as a critical tumor suppressor [10].

Conclusion

Sirtuins promote our health and extend our lifespan by repairing DNA, protecting against neurodegeneration and heart disease, suppressing inflammation, and fighting against tumor growth. These versatile enzymes, ranging from SIRT1 to SIRT7, found in vital organs such as the liver and kidneys to mitigate stress and inflammatory reactions, highlighting their systemic importance. By modulating key molecular pathways and transcription factors, sirtuins not only delay the aging process but also enhance our quality of life by preventing age-related diseases. 

References

1. Ziętara, P., Dziewięcka, M., & Augustyniak, M. (2022). Why Is Longevity Still a Scientific Mystery? Sirtuins-Past, Present and Future. International journal of molecular sciences, 24(1), 728. https://doi.org/10.3390/ijms24010728
2. Park S., Chung M.-J., Son J.-Y., Yun H.H., Park J.-M., Yim J.-H., Jung S.-J., Lee S.-H., Jeong K.-S. The Role of Sirtuin 2 in Sustaining Functional Integrity of the Liver. Life Sci. 2021;285:119997. doi: 10.1016/j.lfs.2021.119997.
3. Wang X., Liu R., Zhang W., Hyink D.P., Das G.C., Das B., Li Z., Wang A., Yuan W., Klotman P.E., et al. Role of SIRT1 in HIV-Associated Kidney Disease. Am. J. Physiol.-Ren. Physiol. 2020;319:F335–F344. doi: 10.1152/ajprenal.00140.2020.
4. Grabowska, W., Sikora, E., & Bielak-Zmijewska, A. (2017). Sirtuins, a promising target in slowing down the ageing process. Biogerontology, 18(4), 447–476. https://doi.org/10.1007/s10522-017-9685-9
5. Watroba, Mateusz, and Dariusz Szukiewicz. “Sirtuins at the service of healthy longevity.” Frontiers in Physiology 12 (2021): 724506.
6. Pan, Z., Dong, H., Huang, N., & Fang, J. (2022). Oxidative stress and inflammation regulation of sirtuins: New insights into common oral diseases. Frontiers in physiology, 13, 953078. https://doi.org/10.3389/fphys.2022.953078
7. Vachharajani, V. T., Liu, T., Wang, X., Hoth, J. J., Yoza, B. K., & McCall, C. E. (2016). Sirtuins Link Inflammation and Metabolism. Journal of immunology research, 2016, 8167273. https://doi.org/10.1155/2016/8167273 
8. Haigis MC, Deng CX, Finley LWS, Kim HS, Gius D. SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res. 2012;72(10):2468–2472.  
9. Bell, E. L., Emerling, B. M., Ricoult, S. J., & Guarente, L. (2011). SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene, 30(26), 2986–2996. https://doi.org/10.1038/onc.2011.37
10. Guo, Zhenyang, Peng Li, Junbo Ge, and Hua Li. “SIRT6 In aging, metabolism, inflammation and cardiovascular diseases.” Aging and disease 13, no. 6 (2022): 1787.

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