Activation of SIRT3 by the NAD+ Precursor Nicotinamide Riboside Protects from Noise-Induced Hearing Loss

Abstract

SUMMARY Intense noise exposure causes hearing loss by inducing degeneration of spiral ganglia neurites that innervate cochlear hair cells. Nicotinamide adenine dinucleotide (NAD+) exhibits axon-protective effects in cultured neurons, however, its ability to block degeneration in vivo has been difficult to establish due to its poor cell permeability and serum instability. Here, we describe a strategy to increase cochlear NAD+ levels in mice by administering nicotinamide riboside (NR), a recently described NAD+ precursor. We find that administration of NR, even after noise exposure, prevents noise-induced hearing loss (NIHL) and spiral ganglia neurite degeneration. These effects are mediated by the NAD+-dependent mitochondrial sirtuin, SIRT3, since SIRT3-overexpressing mice are resistant to NIHL and SIRT3 deletion abrogates the protective effects of NR and expression of NAD+ biosynthetic enzymes. These findings reveal that administration of NR activates a NAD+-SIRT3 pathway that reduces neurite degeneration caused by noise exposure.

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects

“…We then assessed whether NR, as an NAD + precursor that functions as a SIRT3 agonist (34), could replicate the fasting phenotype. We first confirmed NR SIRT3 specificity, showing that this compound blunted the inflammasome in control siRNA THP-1-derived macrophages but not in the SIRT3 siRNA THP-1-derived macrophages ( Figure 6A).…”

Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells

“…Such a high sensitivity and efficiency to use minute amounts of NAR (and somewhat higher concentrations of NR) indicates that these nucleosides could become an essential source for cells starved for other NAD precursors. Considering the positive effects of systemic NR application, for example, in mouse models of pathologies (13)(14)(15)(16)(17), it seems conceivable that generation or utilization of NAR or NR may be affected in these conditions, further pointing to an important physiological role of these processes.…”

“…For example, in a mouse model of Alzheimer disease, NR treatment significantly increased the NAD level in the cerebral cortex and improved cognitive function (13). Moreover, NR protected from noise-induced hearing loss and spiral ganglia neurite degeneration in mice (14). The nucleoside also prevented weight gain in mice challenged with a high fat diet (15).…”

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

“…Whole-body Sirt3-transgenic (wSirt3-Tg) mice were generated by crossing loxP-stop-LoxP-SIRT3.Flagtransgenic mice with mice expressing Cre under the control of the human ␤-actin promoter as described elsewhere (17).…”