Mechanisms of Aging in Age-Related Hearing Loss
Hearing loss emerges from the loss of sensory hair cells in the inner ear, or from the loss of axonal connections between these cells and the brain. It remains somewhat unclear as to which of these losses is the more important; the evidence is mixed. Age-related hearing loss is age-related because the accumulated damage of aging creates a hostile environment for hair cells and their axons. The precise mechanisms of dysfunction are debated, which are more or less important. The development of therapies is at the present time focused on replacement of hair cells rather than on addressing the root causes of hair cell and axon loss.
Age-related hearing loss (ARHL), recognized as the third most common chronic geriatric disease, affects approximately half of adults aged 85 years and over, significantly impairing the health and well-being of the elderly population, leading to communication challenges, social isolation, and cognitive decline. The relationship between aging and ARHL is complex, as the same molecular and cellular mechanisms that drive the aging process also contribute to the deterioration of auditory function. As the body ages, the auditory system becomes increasingly susceptible to the cumulative effects of multiple degenerative processes associated with aging, leading to the progressive hearing loss characteristic of ARHL. Despite advancements in identifying the age-related cellular and molecular changes in the inner ear, the long-standing question that remains is which precise mechanisms underlie the age-dependent degeneration of cochlear structure and function, as well as which methods can be used to preserve or reverse these processes.
Dysregulation of cellular pathways like senescence, autophagy, and oxidative stress, in addition to molecular pathways regulated by AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor-1 (IGF-1), and sirtuins (SIRTs) have each been implicated in hearing loss progression, but the specific causative factors and their direct roles on molecular and cellular pathways that lead to cochlear degeneration are not fully elucidated. Understanding how these pathways affect postmitotic hair cells, the stria vascularis, and the spiral ganglion cells is vital for elucidating the mechanisms of ARHL and developing therapeutic interventions to prevent or mitigate ARHL.
Calorie restriction (CR), well recognized for its healthspan and lifespan-extending properties, has also been shown to slow ARHL in both rodents and primates, but the specific molecular pathways modified by CR in the inner ear and the most effective CR mimetic compounds remain unclear. However, molecules targeting oxidative stress and mitochondrial dysfunction or using CR mimetics such as metformin and nicotinamide mononucleotide (NMN), as well as the potential of senolytics or senomorphics, may offer new treatment strategies for ARHL. Characterizing these fundamental aging pathways will not only enhance our understanding of general aging processes but also illuminate their role in ARHL.