Serum NAD+ is a Weak Predictor of Sensorineural or Age-related Hearing Loss in the Elderly

We were interested to read the article by Sakata et al. on a single-center observational study investigating the relationship between serum NAD+ levels and diacron reactive oxygen metabolites (DROM) and biological antioxidant potential (BAP) in patients aged 50 to 79 years and 20 patients aged >80 years with sensorineural hearing loss (SNHL, n=20) or age-related hearing loss (ARHL, n=20) [1] .NAD+ was reduced in >80-year-old patients with SNHL and patients with ARHL [1] .For every 1 M increase in NAD+ levels, the likelihood of developing SNHL decreased, and every 1 U.CARR increase in dROMs was associated with a 1.01-fold increase in the risk of developing SNHL [1] .There was no association between whole blood NAD+ and dROMs or BAP levels [1] .The study is appealing, but some points should be discussed.The first point is that reactive oxidative (ROS) production is particularly high in disorders due to impairment of the respiratory chain, oxidative phosphorylation or beta-oxidation [2] .Have patients with SNHL/ARHL been examined for these disorders and were the blood parameters for antioxidant capacity against ROS (e.g.superoxide radical (-O2-), hydrogen peroxide (H2O2), singlet oxygen, hydroxyl radical (-OH) and peroxyl radicals (-ROO-) or for reactive oxygen and nitrogen species (RONS) (e.g.NO, peroxynitrite (ONOO-)) normal or reduced in these patients [3] ?The second point is that the group sizes were too small to draw definitive conclusions about the significance of the results.To assess whether NAD+ is indeed reduced in senescent SNHL/ARHL patients, a multicenter design with larger group sizes and homogeneous clinical presentation is needed.The third point is that it was not explained why NAD+ was reduced in senescent SNHL/ARHL patients [1] .Was this due to decreased production of NAD+, increased metabolization, or increased elimination/excretion of the compound?NAD+ is mainly produced by the tricarboxylic cycle, also known as the Krebs or citrate cycle, and glycolysis [4] .Was there any evidence of liver or kidney disease in patients with reduced NAD+?The fourth point is that it was not stated whether SNHL occurred as an isolated symptom or together with other medical problems.It is crucial to know whether SNHL / ARHL was isolated or syndromic, as aetiology, treatment and outcome can differ greatly between these two manifestations.The fifth point is that SNHL may be due to cerebral disease [5] .Therefore, it is imperative that all patients with SNHL undergo thorough cerebral imaging by MRI to avoid overlooking a cerebral cause of SNHL.Of particular interest is whether or not central auditory pathways or auditory processing centers are affected.Cerebral diseases associated with SNHL include small vessel disease [5] , ischemic stroke [6] , scrub typhus or Moya-Moya disease [7] .In summary, it can be said that this interesting study has limitations that relativize the results and their interpretation.Removing these limitations could strengthen the conclusions and reinforce the message of the study.All open questions need to be clarified before readers can uncritically accept the conclusions of the study.A more appropriate study design and additional investigations need to be conducted to determine the underlying cause before drawing definitive conclusions about the impact of reduced NAD+ levels in elderly patients with SNHL or ARHL.