The long term objectives of this research protocol are to: 1) Investigate age related cochlear microcirculatory changes; 2) study molecular biologic changes in age related hearing loss (presbycusis), and 3) attempt to attenuate presbycusis via free oxygen radical scavenging and blocking agents. It has been demonstrated that in the elderly population there is significantly decreased flow within the circulatory system. This proposal will investigate related changes in cochlear vascular permeability, red blood cell velocity, and vessel diameter that may account for this reduction in blood flow. Intravital microscopic techniques will be employed to asses cochlear vascular changes. Prolonged periods of reduced blood flow such as those accompanying aging lead to the formation of tissue damaging free oxygen radicals (FOR). FORs have been implicated as mediators in mitochondrial DNA damage including the generation of mitochondrial DNA deletions (mt DNA del). MtDNA del have associated with cellular and tissue dysfunction, senescence and death. This sequence of events is the foundation of the membrane hypothesis of aging (MHA). The second series of experiments is designed to assess age related changes in cochlear mtDNA del. Polymerase chain reaction will be used to assess changes in cochlear mtDNA del. Studies have demonstrated that loss of auditory sensitivity following ischemia/reprefusion injury can be attenuated by blockers of FOR production (allopurinol), scavengers of FOR (Superoxide-dismutase) and lipid peroxidation inhibitors (Tirilazad mesylate and U74389F) (Seidman et al, 1991, a,b; Seidman et al, 1993). These studies support the role of FOR induced cochlear damage. The third series of experiments will assess the effect of allopurinol ( a blocker and potentially a scavenger of FORs), superoxide-dismutase (SOD a scavenger of FORs), and U74389F (a lazaroid which acts by inhibiting lipid peroxidation), on age related hearing loss. Auditory brainstem response a (ABR) will be used to assess auditory sensitivity. The health relatedness of this project is realized by considering the more than 30 million Americans who suffer from significant sensori-neural hearing loss. As our population ages this number increases rapidly. In the United States today, 23% of the population, between 65 and 75 years, are affected by hearing loss and 40 % of the population, 75 years and above, is affected. In 1980 it was estimated that 11% of the population was 76 years or older. This number is expected to increase to nearly 21% by the year 2030.
