Music to Your Ears: NMN Protects Hearing Cells From Chemotherapeutic Damage

Research in anti-aging has begun to unravel how to keep cells running at their youthful levels for extended periods. At the heart of this process is nicotinamide adenine dinucleotide (NAD+), a coenzyme that is vital for cells, playing a role in metabolism, health, survival, and aging. For this reason, NAD+ has become an important target for studies seeking to find ways to promote healthy aging and longevity while preventing damage done by toxins, from environmental pollutants to medications causing dangerous side effects, such as chemotherapy drugs. 

Recently, a group of Chinese researchers used modulators of NAD+ levels to protect mice from inner ear damage typically caused by certain chemotherapeutics. Researchers from Sun Yat-sen University in China show that ototoxicity — treatment-induced damage to the cells that sense sound and balance that reside in the ear — caused by a chemotherapeutic can be prevented with modulators of NAD+ levels, including a direct precursor called nicotinamide mononucleotide (NMN). This research supports the use of NAD+ boosters like NMN to help patients retain their hearing and balance that is often lost with cancer treatment.

NAD+ supports life and regulates aging

NAD+ is so important for maintaining life, that it is present in every single cell in our bodies. Without NAD+, cells cannot perform the most basic, essential functions. Even though NAD+ is vital, we do not have an unlimited supply of this coenzyme; levels of NAD+ decline dramatically with age (1). Since many diseases are linked to aging, NAD+ is an important target for a huge array of medical conditions and might be the key to preventing certain diseases and premature aging.

One way to ensure the cellular environment is rich with NAD+ is to provide cells with precursors, or modulators, of NAD+. Cells can convert NMN into NAD+ in a series of biosynthetic processes. These processes are quick and efficient — research shows that freshly produced NAD+ can be detected in tissues within 60 minutes of making NMN available (2).

NAD+ is a coenzyme for many proteins, meaning that it is required for these molecular machines to execute their functions. One such family of proteins is the sirtuins, a group of enzymes that regulate cell health, survival, and adaptation to ever-changing conditions. In essence, for a cell to fulfill its purpose, it needs sirtuins to be on point, and this requires a consistent supply of NAD+.

Protecting against chemotherapy damage through NAD+

Since sirtuins keep cells running, and NAD+ is critical for sirtuin activation, a group of researchers out of Guangzhou, China, explored how sirtuins might protect cells from toxic damage. Their findings were recently published in the journal Toxicology Letters (4). For the study, the researchers focused on ototoxicity, which is common among patients receiving chemotherapy with the drug cisplatin.

After showing that cisplatin causes decreases in NAD+ levels in the ear cells that sense sound (hair cells), Yang and colleagues tested if increasing the supply of NAD+ could activate sirtuins and prevent the hearing loss caused by chemotherapy. By promoting NAD+ production in ear cells from fish and mice exposed to cisplatin with modulators like NMN, they found that NAD+ activated sirtuins and prevented ototoxicity. To boot, when a sirtuin inhibitor was administered on top of the NAD+ modulators, the protection against ototoxicity induced by cisplatin was lost.

So how does keeping NAD+ levels from dropping with NMN protect from chemotherapeutic damage? The authors believe that extra NAD+ levels gave cells a boost in energy production, and sirtuin activation improved cellular function and promoted protective measures in the ear cells. In other words, the cells were prepped and ready to face chemotherapy, and they survived in working order.

These results highlight the relationship between NAD+ and sirtuins. Maintaining levels of NAD+ can help cells face the challenges of toxins and aging. This research lays the groundwork for future studies in humans that will explore further protective effects of NAD+.

References:

1. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A. 2015;112(9):2876-2881. doi:10.1073/pnas.1417921112

2. Grozio A, Mills KF, Yoshino J, et al. Slc12a8 is a nicotinamide mononucleotide transporter [published correction appears in Nat Metab. 2019 Jul;1(7):743]. Nat Metab. 2019;1(1):47-57. doi:10.1038/s42255-018-0009-4

3. Roichman A, Elhanati S, Aon MA, et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat Commun. 2021;12(1):3208. Published 2021 May 28. doi:10.1038/s41467-021-23545-7

4. Zhan T, Xiong H, Pang J, et al. Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity [published online ahead of print, 2021 Jun 4]. Toxicol Lett. 2021;349:115-123. doi:10.1016/j.toxlet.2021.05.013