CO ameliorates cellular senescence and aging by modulating the miR-34a/Sirt1 pathway

Abstract

Oxidative stress is recognised as a key factor that can lead to cellular senescence and aging. Carbon monoxide (CO) is produced by haemoxygenase-1 (HO-1), which exerts cytoprotective effects in aging-related diseases, whereas the effect of CO on cellular senescence and aging has not been elucidated. In the current study, we clearly demonstrated that CO delays the process of cellular senescence and aging through regulation of miR-34a and Sirt1 expression. CO reduced H₂O₂-induced premature senescence in human diploid fibroblast WI-38 cells measured with SA-β-Gal-staining. Furthermore, CO significantly decreased the expression of senescence-associated secretory phenotype (SASP), including TNF-α IL-6, and PAI-1 and increased the transcriptional levels of antioxidant genes, such as HO-1 and NQO1. Moreover, CO apparently enhanced the expression of Sirt1 through down-regulation of miR-34a. Next, to determine whether Sirt1 mediates the inhibitory effect of CO on cellular senescence, we pre-treated WI-38 cells with the Sirt1 inhibitor Ex527 and a miR-34a mimic followed by the administration of H₂O₂ and evaluated the expression of SASP and antioxidant genes as well as ROS production. According to our results, Sirt1 is crucial for the antiaging and antioxidant effects of CO. Finally, CO prolonged the lifespan of Caenorhabditis elegans and delayed high-fat diet-induced liver aging. Taken together, these findings demonstrate that CO reduces cellular senescence and liver aging through the regulation of miR-34a and Sirt1.

Keywords:

• Caenorhabditis elegans
• carbon monoxide
• haemoxygenase
• miR-34a
• oxidative stress
• senescence-associated secretory phenotype
• Sirt1

Disclosure statement

All authors have disclosed that they have no conflicts of interest.

Data availability

All relevant data are presented within the paper and its supplementary Information files.

Additional information

Funding

This work was supported by the Priority Research Centres Programme through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2014R1A6A1030318 and NRF-2019R1I1A3A01058874] to H.T.C. and by National Natural Science Foundation of China [No. 81460212] to Min Zheng.

This work was supported by the Priority Research Centres Programme through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2014R1A6A1030318 and NRF-019R1I1A3A01058874] to H.T.C. and by National Natural Science Foundation of China [No. 81460212] to Min Zheng.