Augmentation of cellular NAD⁺ by NQO1 enzymatic action improves age-related hearing impairment

Age-related hearing loss (ARHL) is a major neurodegenerative disorder and the leading cause of communication deficit in the elderly population, which remains largely untreated. The development of ARHL is a multifactorial event that includes both intrinsic and extrinsic factors. Recent studies suggest that NAD⁺ /NADH ratio may play a critical role in cellular senescence by regulating sirtuins, PARP-1, and PGC-1α. Nonetheless, the beneficial effect of direct modulation of cellular NAD⁺ levels on aging and age-related diseases has not been studied, and the underlying mechanisms remain obscure. Herein, we investigated the effect of β-lapachone (β-lap), a known plant-derived metabolite that modulates cellular NAD⁺ by conversion of NADH to NAD⁺ via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD⁺ during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro-inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF-κB, p53, and IDH2. However, augmentation of NAD⁺ by β-lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD⁺ levels by pharmacological agents may be a tangible therapeutic option for treating various age-related diseases, including ARHL.