Roles of Sirtuins in Hearing Protection

Abstract

Hearing loss is a health crisis that affects more than 60 million Americans. Currently, sodium thiosulfate is the only drug approved by the Food and Drug Administration (FDA) to counter hearing loss. Sirtuins were proposed as therapeutic targets in the search for new compounds or drugs to prevent or cure age-, noise-, or drug-induced hearing loss. Sirtuins are proteins involved in metabolic regulation with the potential to ameliorate sensorineural hearing loss. The mammalian sirtuin family includes seven members, SIRT1-7. This paper is a literature review on the sirtuins and their protective roles in sensorineural hearing loss. Literature search on the NCBI PubMed database and NUsearch included the keywords 'sirtuin' and 'hearing'. Studies on sirtuins without relevance to hearing and studies on hearing without relevance to sirtuins were excluded. Only primary research articles with data on sirtuin expression and physiologic auditory tests were considered. The literature review identified 183 records on sirtuins and hearing. After removing duplicates, eighty-one records remained. After screening for eligibility criteria, there were forty-eight primary research articles with statistically significant data relevant to sirtuins and hearing. Overall, SIRT1 (n = 29) was the most studied sirtuin paralog. Over the last two decades, research on sirtuins and hearing has largely focused on age-, noise-, and drug-induced hearing loss. Past and current studies highlight the role of sirtuins as a mediator of redox homeostasis. However, more studies need to be conducted on the involvement of SIRT2 and SIRT4-7 in hearing protection.

Keywords: age-related hearing loss; antioxidant; apoptosis; cochlea; drug-induced hearing loss; noise-induced hearing loss; ototoxicity; outer hair cell; reactive oxygen species.

Figure 1

Flow diagram representing the screening process for articles investigating sirtuins in hearing loss. Created with BioRender.com.

Figure 2

Sirtuin and hearing loss research over time by the number of publications in each sirtuin paralog * Up to May 2024.

Figure 3

Potential roles of sirtuins in hearing loss. SIRT1 and SIRT3 can modulate ROS in the pathologies leading to hearing loss, evidenced by studies in cell cultures and animal models. The major mechanism is the inhibition of intrinsic apoptosis pathway in IHCs, OHCs, and SGNs. Autophagy and mitophagy, which are triggered by pathways involving SIRT1 and SIRT3, can keep the cells under the threshold of caspase-3 activity sufficient for triggering apoptosis, providing protective roles. Inhibition of SIRT2 may be beneficial in NIHL. It is unclear if SIRT4, SIRT5, and SIRT6 are involved in hearing loss or hearing protection. Created with BioRender.com.