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Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer's and Parkinson's disease. It has also been beneficial against noise-induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.

Ageing is known to be the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. They are currently incurable and worsen over time, which has broad implications in the context of lifespan and healthspan extension. Adding years to life and even to physical health is suboptimal or even insufficient, if cognitive ageing is not adequately improved. In this review, we will examine how interventions that have the potential to extend lifespan in animals affect the brain, and if they would be able to thwart or delay the development of cognitive dysfunction and/or neurodegeneration. These interventions range from lifestyle (caloric restriction, physical exercise and environmental enrichment) through pharmacological (nicotinamide adenine dinucleotide precursors, resveratrol, rapamycin, metformin, spermidine and senolytics) to epigenetic reprogramming. We argue that while many of these interventions have clear potential to improve cognitive health and resilience, large-scale and long-term randomised controlled trials are needed, along with studies utilising washout periods to determine the effects of supplementation cessation, particularly in aged individuals. [ABSTRACT FROM AUTHOR]

There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polβ +/- . The 3xTgAD/Polβ +/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ +/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD., Competing Interests: Conflict of Interest Statement V.A.B. had a material CRADA agreement with ChromaDex, Inc.

Aim: To study the changes in the distribution of and the transcriptional levels associated with α4- and α7-subtype nicotinic acetylcholine receptors (nAChRs) in the primary somatosensory (S1) and motor (M1) cortices of rats after electrical stimulation of the basal forebrain (BF)., Material and Methods: Immunofluorescence (IF) analyses were performed on brain sections from 20 rats (experimental groups: controls, contralateral, and ipsilateral to BF stimulation). The nAChR receptor complexes were labeled with antibodies and counted (N) in the cortical layers of the hindlimb representation (S1HL), barrel field (S1BF), and M1. To determine the relative transcriptional mRNA levels, qRT-PCR was performed with tissue from the associated brain regions of 14 different animals in two groups, controls and BF stimulation., Results: For all three tested brain regions, N and D (density) of the α7-subtype nAChR increased in both ipsilateral and contralateral hemispheres after BF stimulation. There was no change in N and D of the α4 subtype. Regardless of BF stimulation, N of both subtypes was lower in M1 compared to S1HL and S1BF, and D was highest in layers II-IV. BF stimulation had no significant effect on the relative mRNA levels of both receptor subtypes., Conclusion: The results show an upregulation of the α7-subtype nAChR as a result of BF stimulation, based on receptor-complex counts on IF images. However, this change was not reflected in mRNA levels, which suggest post-translational modifications. Overall, this study suggests structural changes from the effects of cholinergic projections to the somatosensory and motor cortices.