Abstract
Age-related hearing loss (ARHL), a degenerative disorder characterized by age-dependent progressive increase in the threshold of auditory sensitivity, affects 40% of people over the age of 65, and it has emerged as an important social and public health problem. Various factors, including genetic and environmental components, are known to affect both the onset and severity of ARHL. In particular, age-dependent changes in cellular oxidative stress and inflammatory responses accompanied by altered cellular signaling and gene expression progressively affect the function of the auditory system and eventually lead to hearing impairment. Recent findings suggest that a disturbance of intracellular NAD(+) levels is clinically related to the progression of age-associated disorders. Therefore, maintenance of optimal intracellular NAD(+) levels may be a critical factor for cellular senescence, and thus, understanding its molecular signaling pathways would provide critical insights into the prevention and treatment of ARHL as well as other age-related diseases. In this review, we describe the role of NAD(+) metabolism in aging and age-related diseases, including ARHL, and discuss a potential strategy for prevention or treatment of ARHL with a particular interest in NAD(+)-dependent cellular pathways.
Highlights
Age-related hearing loss (ARHL), known as presbycusis, is a degenerative disorder characterized by progressive worsening of auditory sensitivity with age
The decrease of NAD+/NADH ratio is attributed to the nicotinamide adenine dinucleotide (NAD+)consuming Poly(ADP-ribose) polymerase 1 (PARP1) hyper-activation induced by the accumulation of ageassociated oxidative damage due to altered redox mechanisms and consequent DNA damage [6]
Since silent mating type information regulation 2 homolog 1 activity is influenced by the NAD+/NADH ratio [8], a significant reduction in the NAD+/NADH ratio in the aging process causes a decrease in SIRT1 activity with age
Summary
Aging refers to a series of time-dependent changes at molecular and cellular levels leading to characteristic phenotypic alterations that negatively affect the function of various organisms. Free radicals or ROS, including superoxide anion, hydrogen peroxide, and hydroxyl radicals, are unavoidable byproducts of cellular respiration They are very unstable, highly reactive, and thereby damage proteins, lipids, and DNA in the target organs. Mitochondria has been reported to play a key role in aging, both as a major source of ROS and a target for their damaging effects, and, mitochondrial oxidative stress appears to be a cause, rather than a consequence [12, 13]. This oxidative stress leads to the damage of mitochondrial molecules such as mitochondrial DNA (mtDNA), lipids, or proteins. Though it is not easy to determine which is a cause or consequence, literary evidences indicate a complex relationship between inflammation and oxidative stress in age-associated diseases
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