BIOLOGICAL MECHANISMS FOR VOCAL SENESCENCE

声音的产生涉及有丝分裂和有丝分裂后的组织。 固有层和上皮是有丝分裂组织，而神经运动组织是非有丝分裂组织。 人类有机体的衰老可以由基本的分子机制控制。 最流行的可能影响衰老的分子机制是1）端粒缩短理论和2）人类基因组不稳定理论（也称为DNA降解或污染理论）。 虽然在动物和细胞研究中有很多研究支持这两个理论，但没有研究表明这两个理论在人类中起作用。 在这两种机制中（稍后在提案中解释），端粒缩短理论可能影响有丝分裂组织衰老，基因组不稳定理论影响非有丝分裂组织衰老。 声音是两种组织的复合体，可以代表观察人类有机体衰老或衰老过程的独特窗口。 本研究将以47个家庭共约500名个体为研究对象，涉及3代人。 这些家族与1984年启动的人类基因组计划中的家族相同。 这些家族被广泛地进行基因分型，一些家族具有超过10，000种已知基因型。 在这项拟议的研究中，端粒缩短和DNA降解的实际个体速率将与年龄的声音特征相关。 此外，本研究还将检查其他器官系统（如呼吸系统、中枢神经系统、内分泌系统、结缔组织和肌肉骨骼系统）衰老的指标。 这些器官系统衰老的测量将与声音衰老的特征进行比较，以了解这些测量如何共同变化。 这将使我们能够确定哪些器官系统和组织的年龄与声音相似，并可能为我们提供衰老的基本机制的线索。 最后，通过对这些家族的系谱分析，将进行基因连锁研究，以确定可能控制声音和可能的其他器官或组织衰老的基因的位点。

The production of voice involves both mitotic and post-mitotic tissue. The lamina propria and epithelium are mitotic tissues, while the neuromotor tissues are non-mitotic. Senescence of the human organism may be controlled by fundamental molecular mechanisms. The most popular of the proposed molecular mechanisms that may influence senescence are the 1) telomere shortening theory and 2) the instability of the human genome theory (also referred to as the DNA degradation or contamination theory.) Although much research supports these two theories in animal and cellular studies, no studies have shown these two theories to be operative in humans. Somewhat inherent in these two mechanisms (explained later in the proposal) is that the telomere shortening theory probably affects mitotic tissue senescence and the genome instability theory affects non-mitotic tissue senescence. The voice, being a composite of both types of tissues, may represent a unique window in which to observe the aging or senescence process of the human organism. About 500 individuals in 47 families involving 3 generations will be the subjects of this research. These families are the same families which make up the Human Genome Project started in 1984. These families are extensively genotyped, some with over 10,000 known genotypes. In this proposed study, actual individual rates of telomere shortening and DNA degradation will be correlated with vocal characteristics of age. Furthermore, this study will examine measures of senescence of other organ systems such as respiratory system, central nervous system, endocrine system, connective tissue and musculoskeletal system. Measures of senescence of these organ systems will be compared to characteristics of vocal senescence to see how these measures co- vary together. This will allow us to determine what organ systems and tissues age similar to voice and possibly will give us clues as to fundamental mechanisms of senescence. Lastly, through pedigree analysis of these families, gene linkage studies will be performed to determine loci for genes that may control senescence of voice and possible other organs or tissues.