Effects of Dietary Restriction and Antioxidants on Presbyacusis

Abstract

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 b...

Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis

“…In mice, most of the attenuation of the oxidative damage by CR occurs in post-mitotic tissues such as brain (17,43). In agreement with these reports, CR reduces levels of mtDNA deletions in the cochlea (44) and delays the onset of AHL in rodents (6,42,44). Thus, we propose that CR slows the cochlear aging process by reducing oxidative DNA damage, thereby reducing levels of Bak-mediated apoptosis in the cochlea (6).…”

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…Studies have shown that CR delays the onset of AHL and reduces cochlear pathology (141,150) by reducing oxidative stress (150), which plays a major role in AHL (73,149). Notably, SIRT3 is required for the beneficial effect of CR in preserving auditory function.…”

Effects of Caloric Restriction on Age-Related Hearing Loss in Rodents and Rhesus Monkeys

“…As for housing regimens, the use of individual housing for all animals in CR studies has been widely used since it allows for the food intake of each animal to be controlled with great accuracy [27]. To investigate the effects of CR on AHL and to monitor the progression of AHL, electrophysiological tests of hearing function, auditory brainstem response (ABR), auditory nerve isoelectric (ANI), middle latency response (MLR), or distortion product otoacoustic emission (DPOAE) tests have been used in laboratory animals [3,[17][18][19][20][28][29][30][31].…”

“…In Japan, people over 65 years of age numbered 25.6 million in 2007 (20.0% of the population) (Statistic Bureau, Ministry of Internal Affairs and Communications of Japan: http://www.stat.go.jp/english/data/jinsui/2.htm) and this elderly population is expected to grow to be 35.9 million (39.0% of the population) in 2050 (National Institute of Population and Social Security Research: http://www.ipss.go.jp/indexe.html). AHL affects nearly half the population between 48 and 92 years of age in Wisconsin [2], and 23% of people between 65 and 75 years of age and 40% of people over 75 years of age in the US [3,4]. Because of the high prevalence of AHL and because the overall number of people with it is rapidly growing as lifespan increases in industrialized nations, AHL is a major social and health problem.…”

“…Previous studies have shown that CR delays the onset of AHL and reduces cochlear pathology in mice [17][18][19][20] and rats [3]. The mechanisms postulated to be responsible for the beneficial effects of CR on aging and AHL include reduced oxidative damage and reduced levels of mtDNA mutations [7][8][9][10][11][12][21][22][23][24][25].…”