BIOLOGICAL MECHANISMS FOR VOCAL SENESCENCE

声音的产生涉及有丝分裂和有丝分裂后组织。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能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)人类基因组理论的不稳定性(也称为DNA降解或污染理论)。尽管许多研究在动物和细胞研究中支持这两种理论，但还没有研究表明这两种理论适用于人类。在这两种机制中，端粒缩短理论可能影响有丝分裂组织衰老，而基因组不稳定性理论影响非有丝分裂组织衰老，这两种机制在一定程度上是内在的。声音是这两种组织的复合体，可以代表一个独特的窗口，在其中观察人类有机体的衰老或衰老过程。本研究以47个家庭、3代人、约500人为研究对象。这些家族是组成1984年开始的人类基因组计划的同一个家族。这些家系有广泛的基因分型，有些有超过10,000个已知的基因分型。在这项拟议的研究中，端粒缩短和DNA降解的实际个体比率将与年龄的发声特征相关。此外，这项研究还将检查其他器官系统的衰老指标，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。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，并可能为我们提供关于衰老的基本机制的线索。最后，通过对这些家系的系谱分析，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.