Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice

Abstract

Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimers and Parkinsons Disease. It has also been beneficial against noise induced hearing loss and in hearing loss associated with premature aging. However, its impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.

Approaches to Mitigate Mitochondrial Dysfunction in Sensorineural Hearing Loss

“…72,86 Cellular NAD + levels decline in the cochlea with age or in response to noise exposure. 5,57 Lastly, the age-dependent decline in Sir-tuin1 expression is observed in the mouse cochlea. 80 Additionally, many DNA-repair disease models such as Cockayne syndrome, xeroderma pigmentosum group A (XPA), and ataxia-telangiectasia with dysregulated NM signaling exhibited both mitochondrial dysfunction and hearing loss phenotype.…”

“…1,17,55,65,70 Remarkably, strategies targeting the components of NM signaling such as PARP inhibition, NAD + supplementation, or Sirtuin1 activation displayed promising benefits on hearing, highlighting the therapeutic potential of this signaling pathway on hearing loss prevention. 5,56,57,72,80 CONCLUDING REMARKS Given the central role of mitochondria in cellular metabolism, it is not surprising that mitochondria are tightly regulated and protected to ensure their proper function. Balancing net ROS production, DNA repair, mitochondrial biogenesis, mitochondrial dynamics, and mitophagy are crucial processes that allow cells to ensure the quality and quantity of the mitochondria based on cellular needs.…”

Metabolic decline in an insect ear: correlative or causative for age-related auditory decline?

“…Separate from the lateral wall, the organ of Corti houses the auditory receptors. Optical measurements within the organ of Corti for the key metabolic enzyme nicotinamide adenine dinucleotide (NAD) show a reduction of its expression ( Okur et al, 2022 ) and function ( Majumder et al, 2019 ). Reduction of NAD gives a good indication of oxidative phosphorylation as one molecule of NADH is oxidized to NAD for every 3 ATP produced in the electron transport chain ( Cooper, 2000 ).…”

Metabolism is correlative not causative for age-related auditory decline in an insect model

“…Four out of seven ARHL-susceptible mouse models have an age-dependant decrease in the endocochlea potential (Ohlemiller, 2009). Separate from the lateral wall, in the organ of Corti, optical measurements of a key metabolic enzyme Nicotinamide adenine dinucleitide (NAD) show a reduction of its expression (Okur et al, 2022) and function (Majumder et al, 2019). Reduction by NAD gives a good indication of metabolism as two NAD molecules are oxidized in the glycolytic pathway, three in each Kreb’s cycle and one in the electron transport chain.…”

“…Four out of seven ARHL-susceptible mouse models have an age-dependant decrease in the endocochlea potential (Ohlemiller, 2009). Separate from the lateral wall, in the organ of Corti, optical measurements of a key metabolic enzyme Nicotinamide adenine dinucleitide (NAD) show a reduction of its expression (Okur et al, 2022) and function (Majumder et al, 2019).…”