title: Biologic activity of mitochondrial metabolites on aging and age-related hearing loss.
abstract: OBJECTIVE
  Compounds that upregulate mitochondrial function in an aging model will improve hearing and reduce some of the effects of aging.
  
  
  BACKGROUND
  Reactive oxygen metabolites (ROM) are known products of oxidative metabolism and are continuously generated in vivo. More than 100 human clinical conditions have been associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular accidents, 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 damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the membrane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several age-related processes. It is the purpose of this article to describe the effects of two mitochondrial metabolites, alpha-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 groups: acetyl-l-carnitine, alpha-lipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline and posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were obtained to assess for mtDNA mutations.
  
  
  RESULTS
  The control group demonstrated an expected age-associated threshold deterioration of 3 to 7 dB in the 6-week study. The treated subjects experienced a delay in progression of hearing loss. Acetyl-l-carnitine improved auditory thresholds during the same time period (p<0.05). The mtDNA deletions associated with aging and presbyacusis were reduced in the treated groups in comparison with controls.
  
  
  CONCLUSIONS
  These results indicate that in the proposed decline in mitochondrial function with age, senescence may be delayed by treatment with mitochondrial metabolites. Acetyl-l-carnitine and alpha-lipoic acid reduce age-associated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair age-induced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energy-producing capabilities.
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, Henry Ford Health System, Detroit, Michigan 48323, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Seidman
authors.forename: M J
authors.initials: MJ
authors.lastname: Khan
authors.forename: U
authors.initials: U
authors.lastname: Bai
authors.forename: N
authors.initials: N
authors.lastname: Shirwany
authors.forename: W S
authors.initials: WS
authors.lastname: Quirk
mesh_terms: D000108:Acetylcarnitine / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D001309:Auditory Threshold / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D003056:Cochlear Nerve / Q000098:blood supply / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D017353:Gene Deletion; D008928:Mitochondria / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011304:Presbycusis / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*; D008063:Thioctic Acid / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial; D005609:Free Radicals; D017382:Reactive Oxygen Species; D000108:Acetylcarnitine; D008063:Thioctic Acid