Biologic activity of mitochondrial metabolites on aging and age-related hearing loss

Hypothesis: Compounds that upregulate mitochondrial function in an aging mo del will improve hearing and reduce some of the effects of aging. Background: Reactive oxygen metabolites (ROM) are known products of oxidati ve metabolism and are continuously generated in vivo. More than 100 human c linical conditions have been associated with ROM, including atherosclerosis , arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular a ccidents, and aging. The ROM are extremely reactive and cause extensive DNA , cellular, and tissue damage. Specific deletions within the mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. These deletions are the result of chronic exposure to ROM. When enough mtDNA dama ge accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the mem brane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several age-related processes. I t is the purpose of this article to describe the effects of two mitochondri al metabolites, cc-lipoic acid and acetyl L-carnitine, on the preservation of age-related hearing loss. Methods: Twenty-one Fischer rats, aged 24 months, were divided into three g roups: acetyl-1-camitine, alpha-lipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional co mpounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline and posttreatment hearing thresholds. Cochlear, brain, and skelet al muscle tissues were obtained to assess for mtDNA mutations. Results: The control group demonstrated an expected age-associated threshol d deterioration of 3 to 7 dB in the 6-week study. The treated subjects expe rienced a delay in progression of hearing loss. Acetyl-l-carnitine improved auditory thresholds during the same time period (p < 0.05). The mtDNA dele tions associated with aging and presbyacusis were reduced in the treated gr oups in comparison with controls. Conclusions: These results indicate that in the proposed decline in mitocho ndrial function with age, senescence may be delayed by treatment with mitoc hondrial metabolites. Acetyl-1-carnitine and alpha-lipoic acid reduce age-a ssociated deterioration in auditory sensitivity and improve cochlear functi on. This effect appears to be related to the mitochondrial metabolite abili ty to protect and repair age-induced cochlear mtDNA damage, thereby upregul ating mitochondrial function and improving energy-producing capabilities.