Age-Related Hearing Loss (Presbycusis)---Cisd2 Deficiency Accelerate the Hearing Defect during Aging Process-Renew

Aging is a progressive functional decline, or a gradual deterioration of physiological function with age, including irreversible age-related process of loss of viability. In human, several aging-related diseases such as neurodegenerative, cardiovascular diseases, diabetes have endangered human life and affected the life quality. Presbycusis, age-related hearing lost (AHL), is the third most disability for aged people worldwide. The World Health Organization (WHO) estimates that in 2025, there will be 1.2 billion people over 60 years of age worldwide, with more than 500 million individuals who will suffer significant impairment from presbycusis. The risk factors of presbycusis are heredity, medical diseases and environmental factors; however, the mechanisms of presbycusis are still unclear. The CISD2 gene is the second member of the protein family containing CDGSH ion sulfur domain and highly evolutionarily conserved. CISD2 gene is located within the region on human chromosome 4q where a genetic component for human longevity has been mapped through a comparative genome analysis of centenarian siblings. Previous studies revealed that loss of Cisd2 leads to growth retardation and a smaller somatotype in mice; there is a 13%, 27% and 41% reduction of body weight at 4-, 8- and 36-weeks old, respectively. The Cisd2 knockout mice revealed that early aging phenotypes are accompanied by a shortened life span with haplo-insufficiency in the heterozygous mice with 100% penetrance for both sexes. Main aging phenotypes are observed including neurons (central and peripheral) and muscle (cardiac and skeletal) degeneration as early as three weeks; and by 8 weeks old, further aging phenotypes are developed. Intriguingly, an age-dependent decrease in Cisd2 expression has been detected during normal aging in both mice and human and a persistent level of Cisd2 achieved by transgenic expression in mice extends their median and maximum lifespan without any apparent deleterious side effects. Cisd2 over-expression also ameliorates age-associated degeneration of the skin, skeletal muscles and neurons. These results clearly reveal that Cisd2 plays a critical role in the control of health and lifespan in mice. Our preliminarily structural and functional analysis indicated that Cisd2 KO mice have age-related hearing loss (presbycusis). Accordingly, we will use the Csid2 KO model to investigate the underlying mechanism of involvement of Cisd2 in the pathophysiology of inner ear (cochlea) and associated nervous system. In this study, we propose the following specific aims, (1) to systematically characterize the phenotypic abnormalities of cochlea, hearing defect and accelerated cell aging in the Cisd2 KO mice; (2) to clarify whether the defect in the inner ear or the central control of nervous system (auditory nerve and brain) is the primary determinant for the aging-related abnormality in hearing function; (3) to understand the causes of age-related hearing defects in the aging models, the Cisd2 knockout and naturally aged; (4) to study the correlation between CISD2 expression level and age-related auditory degeneration in patients. Overall this program will shed light on discovering new medicines regulating the expression of CISD2 gene and its related genes to ameliorate AHL and to promote healthy ageing in the future.