New insights into the complex genetic architecture of age-related hearing loss.

Age-related hearing loss (ARHL), or presbycusis, is a very common sensory disorder resulting from cumulative exposure to environmental factors, biological aging and a significant genetic component. Although most cases of ARHL result from the combined influence of numerous low-effect variants, the increasing number of monogenic forms has shown the importance of rare, highly penetrant mutations in ARHL. Advances in whole-exome and whole-genome sequencing have strengthened the evidence for monogenic contributions, identifying deleterious variants consistent with dominant, recessive, or mitochondrial inheritance patterns. These monogenic cases provide valuable insights into the molecular mechanisms underlying cochlear aging and the vulnerability of sensory cells. To date, several genes have been clearly identified as responsible for familial or sporadic late-onset hearing loss, including KCNQ4, GRHL2, ILDR1, EYA4, MYO6, MYO7A, TECTA, WFS1, CDH23, and TMC1. Mutations in these genes affect diverse biological pathways such as potassium recycling, epithelial integrity, transcriptional regulation, mechanotransduction, extracellular matrix stability, and hair cell maintenance-functions that are fundamental to the long-term preservation of hearing. It is important to note that there is a growing overlap between the genes involved in Mendelian deafness and the susceptibility loci identified in ARHL, suggesting the existence of common molecular mechanisms between early-onset hereditary deafness and some forms of progressive ARHL. Furthermore, new data highlight the role of epigenetic regulation, mitochondrial dysfunction, cochlear synaptopathy, and non-coding RNAs in hearing loss. Despite major advances, several challenges remain, including phenotypic heterogeneity, limited representation of non-European populations, and a lack of consistency in the reproducibility of results across studies. Distinguishing between subtypes of ARHL characterized by audiometry-including sensory, neural and synaptopathic, metabolic forms, will likely be essential for improving genetic analyses and precision medicine approaches. Moreover, although polygenic risk scores (PRS) represent a promising strategy for risk prediction, their clinical applicability remains limited. Overall, the integration of monogenic, polygenic, environmental, and epigenetic data will be essential for understanding the complex genetic architecture of ARHL and for developing future personalized therapeutic interventions.