A MOUSE MODEL OF DELAYED AGING: OXIDATIVE MECHANISMS

延迟衰老的小鼠模型：氧化机制

• 批准号: 6051280
• 负责人: HOLLY M. BROWN-BORG
• 金额: $ 7.07万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6051280
• 关键词: DNA damage; age difference; aging; antioxidants; biological models; biomarker; catalase; enzyme activity; free radical scavengers; free radicals; genetic models; laboratory mouse; liver cells; longevity; messenger RNA; oxidation; oxidative stress; peroxidation; pituitary dwarfism; superoxide dismutase; tissue /cell culture; western blottings

A progressive decline is physiological processes occurs in all organisms. A popular theory to explain this decline involves oxidative stress and subsequent damage to DNA, proteins and lipids. Delaying this decline is associated with extended lifespan. Mice with hereditary dwarfism (Ames dwarf, df/df) exhibit both delayed aging, living more than a year longer than normal siblings (P is less than 0.0001) and differences in antioxidant defense capacity. The objectives of this pilot project are to examine oxidative mechanisms in this mouse model and show that Ames dwarf mice are able to resist oxidative stress resulting in less oxidative damage and delayed aging. The aims of this proposal are: 1) to examine levels of activity (protein, kinetics, mRNA) of enzymes involved in cellular oxidation/recycling (catalase and superoxide dismutase) in tissues from long-living dwarf and normal sibling mice at 3,6,12, 18 and 24 months of age; 2) to evaluate the cellular oxidative response to in vitro oxidative stress in hepatocytes from both groups of mice; and 3) to measure oxidative damage to DNA, proteins and lipids in dwarf and normal mice at different ages. The overall hypothesis is that the Ames dwarf mouse has a biologic advantage over normals with better enzymatic scavenging of toxic metabolic byproducts underlying their enhanced longevity. These studies will generate preliminary data, support earlier observations and further the understanding of the relationship between cellular oxidation and aging in a mammalian model of extended lifespan. The dwarf mutant may be a unique example of a 'gerontogene' in mammalian species. The information gleaned from these preliminary studies will further establish the dwarf as a genetic model of delayed aging and second, may substantiate the dwarf gene as a longevity determinant gene.

在所有生物体中都会发生生理过程。 解释这种下降的一种流行理论涉及氧化应激以及随后对DNA，蛋白质和脂质的损害。 延迟这种下降与延长寿命有关。 具有遗传矮人（Ames矮人，DF/DF）的小鼠表现出延迟的衰老，比正常兄弟姐妹长一年以上（P小于0.0001），抗氧化防御能力差异。 该试验项目的目标是检查该小鼠模型中的氧化机制，并表明艾姆斯矮人小鼠能够抵抗氧化应激，从而导致氧化损伤和延迟衰老。 该提案的目的是：1）检查参与3,6,12、12、18和24个月的组织中，参与细胞氧化/回收酶的活性水平（蛋白质，动力学，mRNA）的酶的酶（蛋白质，动力学，mRNA）和来自长期生存矮小小鼠的细胞氧化/回收（过氧化酶和超氧化物歧化酶）的水平； 2）评估两组小鼠的肝细胞中对体外氧化应激的细胞氧化反应； 3）在不同年龄段的矮人和正常小鼠中对DNA，蛋白质和脂质的氧化损伤。总体假设是，艾姆斯矮人小鼠比正常的具有生物学的优势，其酶促清除的酶促代谢副产品具有更好的寿命。 这些研究将产生初步数据，支持早期的观察结果，并进一步了解延长寿命的哺乳动物模型中细胞氧化与衰老之间的关系。 矮人突变体可能是哺乳动物物种中“天赋”的独特例子。 从这些初步研究中收集的信息将进一步建立矮人作为延迟衰老的遗传模型，其次，可以证实矮基因作为长寿决定性基因。