Exploring mechanisms of aging in eukaryotes

描述（由申请方提供）：本研究的长期目标是通过研究家犬（Canis familiaris）的类似生化和生理变化，更好地了解人类衰老和年龄相关变化的生化、遗传和生理机制。随着美国人口的寿命在上个世纪几乎翻了一番，了解健康老年的生物学机制在经济和社会上都变得越来越重要。通过对导致老年的生物学过程的机械理解，可以推导出一种方法，通过这种方法，越来越老的美国人口也越来越健康。为了理解促进健康长寿的遗传和生化机制，本申请提出利用家犬来研究衰老的自由基理论。工作假设是，氧化应激对衰老过程有很大的贡献，与衰老和长寿相关的特定机制可以通过研究具有自然多样寿命的品种之间的细胞和遗传差异来确定。主要目的是通过研究氧化应激可能影响犬寿命的机制来研究工作假设。因为已经证明氧化应激物影响其他生物体的寿命（Kapahi等人，1999; Campisi等人，2001），阐明应激源在哺乳动物系统中的作用将是至关重要的，哺乳动物系统的医疗护理寿命与人类非常相似（帕克等人，2004年），但寿命明显短于人类。具体来说，我们确定1）如果氧化应激水平与长寿C。familiaris，2）与减少细胞应激相关的主要酶的基因表达水平。建立这种关于原代犬成纤维细胞抗应激能力的强大知识基础，为未来更详细地研究与长寿相关的每个生化途径中的其他参数奠定了基础。此外，保持狗的主人联系，促进纵向数据。

DESCRIPTION (provided by applicant): The long-term objective of this research is to better understand the biochemical, genetic and physiological mechanisms of aging and age related changes in man through investigation of similar biochemical and physiological changes in the domestic dog, Canis familiaris. With life span in the American population nearly doubling in the last century, it is becoming of greater importance both economically and socially, to understand the biological mechanisms allowing for healthy old age. Through a mechanistic understanding of the biological processes contributing to old age, methodology can be derived by which the increasingly older population of Americans is also an increasingly healthier population. Towards the goal of understanding the genetic and biochemical mechanisms promoting healthy longevity, this application proposes the utilization of the domestic dog for investigation of the free radical theory of aging. The working hypothesis is that oxidative stress contributes considerably to the aging process and specific mechanisms associated with aging and longevity can be determined by investigating the cellular and genetic differences between breeds with naturally diverse life span. The primary objective is to investigate the working hypothesis by examining the mechanisms through which oxidative stress may influence longevity in the dog. Because oxidative stressors have been demonstrated to affect longevity in other organisms (Kapahi et al, 1999; Campisi et al., 2001), it will be vital to elucidate the effects of the stressors in a mammalian system whose lifetime of medical care closely resembles the human's (Parker et al., 2004), yet has a life span significantly shorter than the human. Specifically, we determine 1) if oxidative stress levels are correlated to longevity within C. familiaris, 2) the level of gene expression of primary enzymes associated with diminishing cellular stress. Establishing this strong basis of knowledge regarding stress resistance in primary canine fibroblasts sets the stage for future more detailed investigations into the additional parameters within each biochemical pathway determined associated with longevity. Further, owner contact for the dogs is maintained, facilitating longitudinal data.