The proposed studies test mechanism-based, clinically relevant interventions to meet the challenges of aging in the Veteran population. The underlying hypothesis is that prior exposure to noise, such as that which occurs to service members, contributes to the burden of later age-related hearing loss (ARHL) resulting in an earlier onset and a greater hearing impairment. Studies use the UM-HET4 model and test a small arms fire (SAF)-like impulse noise, chosen for military relevance and a 8-16 kHz 100 dB noise, chosen because it has already been shown to accelerate a component of ARHL in the mouse model. Noise (or sham) is given at 4 months of age to model noise during service as a young adult. Four distinct components of ARHL are assessed: 1) loss of sensory cells (hair cells) and associated threshold shifts in auditory brain stem response (ABR), 2) loss of synaptic connections of the auditory nerve (AN) to inner hair cells (IHCs) and associated changes in ABR dynamic range, 3) loss of AN cell bodies, and 4) a temporal processing deficit evidenced by reduced Gap Detection. These are tested at 6, 12, 18 and 24 months of age in Aim 1, comparing mice with and without either of the noise exposures.
Aim 1 : Assess the progression of ARHL in mice receiving noise exposure at 4 months of age compared to age-matched littermates without noise overstimulation. Our goal is to identify mechanism-based treatments to prevent or reduce ARHL and any acceleration and enhancement from prior noise exposure. Treatments tested can be started in mid-life (9 mos. old in mice) to model treatment to Veterans. One treatment targets oxidative stress, using a combination of anti-oxidants (vitamins A, C, E plus magnesium) already shown to reduce noise-induced hearing loss. A second treatment, rapamycin, has been shown in our preliminary studies to reduce age-related loss of cochlear sensory cells (outer hair cells). Both rapamycin and ACEMg are already in clinical application or trails for other purposes. Side-effects of prolonged rapamycin could limit application in veterans.
Aims 2 b and c therefore test a potentially safer rapalog and a potentially safer application period, respectively, to see if they retain efficacy.
Aim 2 a: Determine if ACEMg or rapamycin added to diet at 9 mos. of age will decrease ARHL and/or reduce noise acceleration / enhancement of ARHL (tested using Aim 1 metrics);
Aim 2 b: Determine if use of everolimus, a more mTORC1 specific rapalog or Aim 2c: a later (14 mos.) intermittent (every 2 weeks) application of rapamycin retains efficacy in reducing ARHL.
Aim 3 uses RNA-Seq to identify the functional signaling pathway targets of the rapamycin effect in reducing ARHL towards the goal of providing a basis for identification or development of safer rapalogs Aim 3: Identify age-related changes in cochlear gene expression and the influence of rapamycin on ARHL related functional signaling pathways.
of the Proposed Studies to the VA Patient Care Mission: For many Veterans, Age Related Hearing Loss (ARHL) will act on an auditory system already impacted by noise exposure during their service. Proposed studies examine the impact of prior noise on acceleration and enhancement of ARHL and test treatments to reduce ARHL and prevent any acceleration/enhancement. Hearing Loss is the most common service-related disability for those who served in the gulf wars (Theodoroff et al., 2015; Yankaskas, 2012). A reduced ability to communicate causes dramatic decreases in social integration, employment opportunity and overall quality of life. ARHL also increases the risks from other age-related changes and illnesses and contributes to the incidence of depression and dementia (e.g. Davis and Smith, 2013; Gates et al., 2010). The proposed studies test mechanism based interventions that can be started in mid-life and are well positioned for rapid translation to meet the challenges of aging in the Veteran population.