According to the World Health Organization, one third of the population over 65 years old suffers from age-related hearing loss, also known as presbycusis, making it one of the most common causes of disability in older people. Insulin growth factor type 1 (IGF-1) is a neurotrophic factor fundamental for the regulation of cochlear development, growth and differentiation. Human IGF-1 deficiency is associated with poor growth rates, mental retardation and syndromic hearing loss (OMIM608747). Equally, Igf1-/- mice are barren dwarfs with poor survival rates and congenital profound deafness. Patients with heterozygous IGF1 or IGF1R mutations do not present a clear hearing phenotype, but low levels of IGF-1 are also associated with hearing loss and presbycusis in related human genetic syndromes. Circulating IGF-1 levels decrease physiologically during mammalian aging, and this reduction has been related to human cognitive decline and neurodegeneration. Still the relationship between presbycusis and IGF-1 age-regulated levels has not been studied in depth. The auditory phenotype of young Igf1+/- mice is similar to that of their wild type littermates. However, during the first year of life Igf1+/- mice suffered significant agerelated hearing loss alongside the decrease in the circulating levels of IGF-1. From the age of 6 months, Igf1+/- mice showed higher hearing thresholds and increased susceptibility to environmental stressors like noise when compared to wild type mice. Noise exposure caused an irrecoverable increase of auditory thresholds in heterozygous mice, matched by an exacerbated cellular damage in the cochlea, infiltration of IBA1+ cells and apoptosis. At the molecular level, the chronic IGF-1 haploinsufficiency causes a pro-inflammatory state in the cochlea with higher expression of Tgfb1 and Il1b. After noise exposure, the cochlear inflammatory response increases, accompanied by the hyperactivation of stress-related kinases (JNK) in heterozygous mice, which is maintained even a month after damage. Along these alterations, IGF-1 haploinsufficient mice show a defective activation of prosurvival (AKT), antioxidant and anti-inflammatory routes. These data point to Igf1 as a genetic factor contributing to age-related and noise-induced hearing loss. In summary, genetic mouse models of human IGF-1 deficiency are a valuable tool to study the molecular bases of progressive hearing loss.

Resumen del póster presentado al EMBO Workshop: Molecular mechanisms of ageing and regeneration – From pluripotency to senescence, celebrado en Spetses (Grecia) del 16 al 24 de agosto de 2016.

Peer Reviewed