NMNAT1 Activates Autophagy to Delay D‐Galactose‐Induced Aging in Cochlear Hair Cells

TL;DR

This study shows that NMNAT1 helps delay aging in cochlear hair cells by boosting autophagy, offering a potential target for treating age-related hearing loss.

Contribution

The study reveals a novel role of NMNAT1 in activating autophagy and regulating metabolism to delay cochlear hair cell aging.

Findings

NMNAT1 overexpression activates autophagy and decelerates hair cell aging.

Nmnat1-knockout cells show a dysregulated tricarboxylic acid cycle.

Reduced NMNAT1 expression is observed in D-gal-induced aging models.

Abstract

With an aging population, the incidence of age‐related hearing loss (ARHL) continues to increase. Aging cells exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels and impaired autophagy; however, the mechanisms underlying these processes remain largely unclear. In our study, we assessed the role of nicotinamide nucleotide adenylate transferase 1 (NMNAT1) in cochlear hair cell aging using D‐galactose (D‐gal)‐induced aging HEI‐OC1 cells and cochlear explants. We observed a significant reduction in NMNAT1 expression in HEI‐OC1 cells and cochlear hair cells treated with D‐gal. Notably, NMNAT1 overexpression activated autophagy and decelerated hair cell aging. Metabolomic analysis revealed a dysregulated tricarboxylic acid cycle in Nmnat1‐knockout cells, indicating that NMNAT1 regulates autophagy and metabolic pathways that affect hair cell aging. These findings offer novel insights into the association between autophagy and metabolism during aging and highlight NMNAT1 as a potential therapeutic target for the prevention and treatment of ARHL.

The study presents mechanistic insights into cochlear hair cells aging using cellular and explant models. The assessment into NMNAT1 regulated NAD+ metabolism, autophagy, and aging in ARHL. NMNAT1 overexpression restores autophagic activity and decelerates aging in cochlear hair cells.

Figures