Cellular Mechanisms of Age-Related Hearing Loss

Age-related hearing loss (ARHL) is an exacerbation in the auditory receptor of the accumulation of cellular damage, characteristic of the aging process. In the cochlea, aging damage is likely aggravated by exceptional metabolic requirements and lifelong exposure to noise and other environmental damaging factors, on a background of genetic susceptibility. Genomic damage and instability, along with impaired epigenetic regulation and protein homeostasis, likely are primary causes of cellular aging (Cell 153:1194–1217, 2013). Relative contributions to ARHL still are unclear, although mutations in the mitochondrial genome seem particularly relevant. Primary damage mechanisms trigger defensive responses whose exhaustion leads to failure in cell function associated with aging. Relevant to ARHL are signaling pathways adapting cell growth and metabolism to ongoing needs, including those derived from damage. Insulin-like growth factor-1 (IGF-1), part of a major anabolic regulatory pathway, declines greatly in ARHL. Low levels of sirtuins, enzymes involved in catabolic control by regulating NAD+ levels, are also linked to ARHL. Beneficial effects of caloric restriction in ARHL may be mediated through sirtuin regulation of antioxidation mechanisms. A second most relevant aging defense mechanism which may be central to ARHL is exhausted mitochondrial function. Dysfunctional mitochondria, in connection with mitochondrial genome mutations and high cochlear metabolic demands, leads to excessive free radical buildup and cellular damage and apoptosis. This is likely a major contributor to ARHL, although a primary causative link is still missing. Age-related mitochondrial dysfunction in different cochlear cell types may be at the origin of different ARHL histopathologies. Like in aging in general, the combination of primary causes of damage and exhausted defensive mechanisms leads to the final ARHL phenotype. In this regard, the involvement in ARHL of age-related changes in central auditory pathways, due to a complex combination of limited inputs from the aged cochlea and brain aging, is very relevant. It includes changes in connectivity, synapses, and neurotransmitter systems which add further complexities and challenges to the understanding and management of ARHL.