Effects of dietary restriction and antioxidants on presbyacusis.

Objectives/Hypothesis: The premise of this study is that the membrane hypothesis of aging, also known as the mitochondrial clock theory of aging, is the basis for presbyacusis. Furthermore, it is proposed that treatment with antioxidants or dietary restriction can attenuate age-related hearing loss. Many studies have demonstrated a reduction in blood flow to specific tissues, including the cochlea, with aging. Hypoperfusion leads to the formation of reactive oxygen metabolites (ROM). ROM are highly toxic molecules that directly affect tissues including inner ear structures. In addition, ROM can damage mitochondrial DNA (mtDNA), resulting in the production of specific mtDNA deletions (mtDNA del 4977 [human] or mtDNA del 4834 [rat]; also known as the common aging deletion]. Previous corroborating data suggest that the common aging deletion mtDNA 4834 may be associated not only with aging but also with presbyacusis, thus further strengthening the basis of the current studies. In this study, experiments provide compelling evidence that long-term treatment with compounds that block or scavenge reactive oxygen metabolites attenuate age-related hearing loss and reduce the impact of associated deleterious changes at the molecular level. Study Design: Prospective randomized study. Methods: One hundred thirty rats were randomly assigned to one of six groups with appropriate controls. Animals were divided into the following treatment arms: group 1, 30% caloric restriction; group 2, vitamin E oversupplementation; group 3, vitamin C oversupplementation; group 4, melatonin treatment; group 5, lazaroid treatment; and group 6, placebo. In addition, 10 animals were used to determine the appropriate caloric restriction. All subjects underwent baseline and every-3-month testing until their health failed (range, 18‐28 mo; average, 25 mo). This testing included auditory sensitivity studies using auditory brainstem response (ABR) testing, as well as tissue analysis for mtDNA deletions using molecular biological techniques. At the conclusion of the study, animals underwent a final ABR test and were tested for mtDNA deletions in brain and inner ear tissues, and the opposite ear was used for histological analysis. Results: Results indicated that the 30%-caloricrestricted group maintained the most acute auditory sensitivities, the lowest quantity of mtDNA deletions, and the least amount of outer hair cell loss. The antioxidant-treated subjects had improved auditory sensitivities, and a trend for fewer mtDNA deletions was observed compared with the placebo subjects. The placebo subjects had the poorest auditory sensitivity, the most mtDNA deletions, and the greatest degree of outer hair cell loss. Conclusions: Intervention designed to reduce reactive oxygen metabolite damage appears to protect against age-related hearing loss specifically and aging in general. This is reflected by an overall reduction in mtDNA deletions. These data also suggest that the common aging deletion appears to be associated with presbyacusis, as demonstrated by an increased frequency of the mtDNA del 4834 in the cochleae with the most signifi