Abstract
Age-related hearing loss (ARHL) is the most common form of hearing loss and the predominant neurodegenerative disease associated with aging. Sirtuin 1 (SIRT1) is associated with the most complex physiological processes, including metabolism, cancer onset, and aging. SIRT1 protein levels are enhanced by the conversion of nicotinamide to N1-methylnicotinamide (MNAM), independent of its mRNA levels. Moreover, MNAM has implications in increased longevity achieved through its mitohormetic effects. Nicotinamide N-methyltransferase (Nnmt) is an enzyme involved in MNAM metabolism, and its level increases under caloric restriction (CR) conditions. The CR condition has implications in delaying ARHL onset. In this study, we aimed to determine the relationship between diet, hearing function, SIRT1 and SIRT3 expression levels in the inner ear, and cochlear morphology. Mice fed with a high-fat diet (HFD), HFD + 1% MNAM, and low-fat diet (LFD) were monitored for age-related auditory-evoked brainstem responses, and changes in cochlear histology, metabolism, and protein and mRNA expressions were analyzed. Our results revealed that the HFD- and aging-mediated downregulated expression of SIRT1 and SIRT3 promoted hearing loss that was obfuscated by MNAM supplementation-induced upregulated expression of cochlear SIRT1 and SIRT3. Thus, our results suggest that MNAM can be used as a therapeutic agent for preventing ARHL.
Highlights
Age-related hearing loss (ARHL) is a multifactorial disease that results from a combination of genetic predispositions and effects of the aging process, including a plethora of insults to the auditory organ throughout an individual’s lifetime (Gates and Mills, 2005; Yamasoba et al, 2013)
Considerable differences were not observed among the YHFD, YHFD-MNAM, and YLFD groups, the body weights of the OHFD mice markedly increased compared with both the OLFD mice and OHFD-MNAM mice groups (Supplementary Figures 1A,B)
The OHFD mice presented with significantly higher serum cholesterol and triglyceride levels compared with the other groups, probably because the low-fat diet (LFD) and MNAM supplementation included with the high-fat diet (HFD) prevented such increases in these groups (Supplementary Figure 1C)
Summary
Age-related hearing loss (ARHL) is a multifactorial disease that results from a combination of genetic predispositions and effects of the aging process, including a plethora of insults to the auditory organ throughout an individual’s lifetime (Gates and Mills, 2005; Yamasoba et al, 2013). Consumption of a high-fat diet (HFD) causes a decrease in SIRT1 expression (Wang et al, 2011; Chalkiadaki and Guarente, 2012) and damages metabolic changes such as glucose intolerance, insulin resistance, hepatic lipid accumulation and inflammation, and macrophage accumulation in the adipose tissue This results in enhanced mitochondrial function, shortening of the lifespan (Chalkiadaki and Guarente, 2012), and early onset of ARHL in C57BL/6 (B6) and CBA/J mice (Le Prell et al, 2011; Du et al, 2012). We investigated its expression and roles in hearing function and the associated morphological changes in the cochlea using HFD, HFD + 1% MNAM (HFD-MNAM), and low-fat diet (LFD) aging B6 mice
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