Dietary Zinc Glycine Supplementation Attenuates Aging-Driven Cochlear Hair Cell Oxidative Injury and Hearing Loss

Background: Micronutrient imbalance is now recognized as a modifiable risk factor driving the progression of age-related hearing loss (ARHL). Zinc, an indispensable dietary trace nutrient, acts as a structural cofactor and transcriptional regulator of a broad panel of antioxidant enzymes to sustain systemic and cellular antioxidant defense capacity. Nevertheless, the therapeutic value of zinc nutritional supplementation and its precise molecular mechanisms against age-dependent cochlear degeneration remain largely uncharacterized. Methods: We established aging mouse models to observe the phenotypic changes caused by disrupted cochlear zinc nutritional homeostasis, and applied oral supplementation of bioavailable zinc glycinate to intervene in ARHL. In vitro D-galactose (D-gal) stimulation was adopted to induce cellular oxidative damage, followed by a series of mechanistic assays to detect the expression of core antioxidant molecules and determine mitochondrial function. Results: Disrupted cochlear zinc nutritional homeostasis induced progressive hearing loss and severe hair cell degeneration in aging mice. Conversely, oral zinc glycinate supplementation significantly relieved age-related hearing decline and reduced oxidative injury of cochlear hair cells. As a nutritional intervention, zinc glycinate significantly elevates the levels of key intracellular antioxidants (SOD, GSH, and GPX4) and rescues mitochondrial dysfunction induced by D-galactose triggered reactive oxygen species accumulation. Moreover, the protective effect of zinc glycinate may be associated with the upregulation of metal-responsive transcription factor 1 (MTF-1), which in turn suppresses the D-galactose-induced hyperactivation of the pro-inflammatory cGAS-STING pathway. Conclusions: Dietary zinc glycinate supplementation offers potential protection against cochlear aging. This auditory benefit may involve MTF-1 upregulation and inhibition of the cGAS-STING pathway. Collectively, these findings provide preclinical evidence supporting further investigation of zinc glycinate as a potential nutritional intervention for ARHL.