NAD+ improves age-related hearing loss in mice

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In a preprint published in bioRxiv, scientists showed that long-term supplementation with nicotinamide riboside (NR), a precursor to NAD+, attenuates the progression of age-related hearing loss in a mouse model [1].

An unrecognized hearing loss

Globally, age-related hearing loss (ARHL) is the most common sensory deficit in older people. In addition, it is associated with several problems, including cognitive decline, social isolation and the risk of accidents. However, due to its insidious progression, the disease often goes unrecognized.

The etiology of ARHL is still poorly understood. Some of the proposed hypotheses involve age-related changes in accumulation of DNA damage (genomic instability), oxidative stress, mitochondrial dysfunction, and inflammation associated with senescence. [2].

NAD+ and hearing

NAD+, a natural co-enzyme, which has been shown to improve certain characteristics of aging and several age-related conditions, also plays a role in the auditory system. For example, researchers have previously shown that NAD+ supplementation prevents the progression of hearing loss in a mouse model of premature aging. [3]. This led them to conduct this experiment in wild-type mice, in which they expected similar results.

NAD+ in the cochlea

In this article, the researchers compared the cellular levels of NAD+ in the cochleas of young (2 months) and old (12 months) mice and found that total NAD+ and relative NAD+/NADH levels were lower in the cochleas of mouse. older animals. This led researchers to hypothesize that long-term NR supplementation could reverse the age-related reduction of this essential co-enzyme.

NR prevents and attenuates the progression of ARHL in mice

To determine the effects of long-term administration of NR on hearing loss in aged mice, researchers administered NR in the drinking water of a treatment group, with a control group receiving unmodified water . Both groups were then tested for their hearing ability using an auditory brain response (ABR) system at 2, 8 and 12 months of age.

Supplementation was found to prevent ARHL progression specifically at high sound frequencies (16 and 32 kHz). Another test, hearing threshold shift, showed that NR even improved high-frequency hearing in a subset of treated mice.

In addition to the preventive benefits, the researchers wanted to determine whether NR could also improve disease progression even after hearing loss. To address this issue, mice with confirmed ARHL at 15 months of age were treated with NR for 1.5 months.

Unfortunately, the ABR results showed no change in the hearing thresholds of this group at any given frequency. However, when individual threshold changes were studied, administration of NR in the female subgroup resulted in a significant reduction in threshold changes at 24 kHz. These results suggest that NR, even when administered later in life, still benefits already affected mice at certain frequencies.

Lipids as protectors

To investigate the underlying effects of NAD+ on ARHL, the team used RNA sequencing (RNA-seq) to determine the transcriptomic profiles of cochleae in the treated and untreated groups. Surprisingly, mitochondrial-bound RNA profiles were not significantly altered, meaning that the reparative effects might not be explained by a direct role of NAD+ in mitochondrial homeostasis.

However, they found that NR acted along the PPARγ-CIDEC, -PLIN1, -PCK1 axis, which is potentially related to lipid droplet formation. Combined with evidence that lipid droplets could reduce excessive reactive oxygen species, this led to the hypothesis that NR administration indirectly affects mitochondrial homeostasis and function via this mechanism, thereby protecting cochlear cells from cytotoxic damage.

Conclusion

Age-related hearing loss is one of the most common and burdensome diseases in older people. In a mouse model, long-term nicotinamide riboside supplementation can increase the level of NAD+ in the cochlea while preventing and arresting ARHL. This suggests a potential new treatment for age-related hearing loss, and it encourages further studies that translate this evidence in mice into clinical application.

Literature

[1] Okur, MN et al. Long-term NAD+ supplementation prevents progression of age-related hearing loss in mice. bioRxiv2022.2008.2025.505332, doi: 10.1101/2022.08.25.505332 (2022).

[2] Wang, J. & Puel, JL Presbycusis: an update on cochlear mechanisms and therapies. J Clin Med 9doi:10.3390/jcm9010218 (2020).

[3] Okur, MN et al. Short-term NAD(+) supplementation prevents hearing loss in mouse models of Cockayne syndrome. NPJ Aging Mech Dis 61, doi: 10.1038/s41514-019-0040-z (2020).

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