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

Abstract

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.

G6PD overexpression protects from oxidative stress and age‐related hearing loss

“…However, no differences were observed in Pgc1α or its downstream targets Nrf1 and Tfam . As recently reported by (Kim et al, 2019), enhanced Sirt1 expression could limit PARP1 activation by decreasing the NAD + pool in the 3‐ and 9‐month‐old G6PD ‐Tg cochleae.…”

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex

“…The rats in the simulated ageing groups accumulated more MDA than those in the corresponding control groups, and GSH content and SOD activity demonstrated opposite change trends. Many previous studies have indicated that oxidative stress is closely related to the occurrence and development of central presbycusis, consistent with the results of our study [53][54][55]. ROS destroy cell function, destroy normal tissues and cells and affect normal osmotic pressure, further leading to metabolic disorders of important organs and eventually to overall ageing [56][57][58].…”

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…337,344,345 Augmentation of NAD + by β-lap, a potent substrate of NQO1, effectively prevents ARHL and its accompanying harmful effects by preventing oxidative stress and inflammation and improving mitochondrial function in rodents. 346 Moreover, mounting evidence has shown that NAD + -dependent sirtuins can extend the lifespan of yeast, worms, flies and mice and alleviate many diseases of aging-related pathologies. For instance, both brain-specific or whole-body SIRT1-overexpressing transgenic mice exhibit a slowed aging and a prolonged lifespan.…”