A Novel p16INK4a Reporter System to Assess Aging In Vivo

一种评估体内衰老的新型 p16INK4a 报告系统

• 批准号: 7989758
• 负责人: Christin E Burd
• 金额: $ 7.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989758
• 关键词: Address; Age; Age of Onset; Aging; Aging-Related Process; Alleles; American; Animals; Autoimmunity; Behavior Therapy; Biological; Biological Aging; Biological Assay; Biological Markers; Biological Models; Bioluminescence; CDKN2A gene; Caloric Restriction; Cardiovascular Diseases; Cell Aging; DNA Damage; Data; Detection; Development; Disease; Elderly; Embryo; Environmental Risk Factor; Event; Exercise; Fatty acid glycerol esters; Fibroblasts; Firefly Luciferases; Gene Expression; Goals; Health; Human; In Vitro; Incidence; Individual; Ionizing radiation; Kinetics; Knock-in Mouse; Life; Link; Longevity; Luciferases; Malignant Neoplasms; Measures; Methods; Modeling; Moderate Exercise; Molecular; Monitor; Mus; Nature; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organ Specificity; Pancreas; Pattern; Physiological; Population; Premature aging syndrome; Primates; Process; Property; Reading; Regulation; Reporter; Research; Rodent; Running; Specificity; System; Testing; Time; Tissues; Western Blotting; Work; age related; anti aging; cell age; cell type; chromatin immunoprecipitation; chromatin modification; design; diet and exercise; dietary restriction; human subject; in vivo; insight; mouse model; novel; promoter; public health relevance; senescence

DESCRIPTION (provided by applicant): The incidence of age-related diseases continues to rise as the number of Americans over the age of 65 grows. As a result, research is now focused on discovering methods to promote longevity. Although few molecular indicators of biological age have been indentified, we and others have recently shown that p16INK4a serves a robust and accurate marker of mammalian aging. Induction of p16INK4a correlates directly with chronological age in rodents and can be slowed by anti-aging strategies such as caloric restriction. In addition, our preliminary data show that p16INK4a levels are decreased by moderate exercise in healthy human subjects. Despite these data, the mechanisms by which lifestyle modification promotes longevity remain largely undefined. Herein, I will exploit the unique properties of p16INK4a as an aging biomarker to assess the tissue- specificity of anti-aging strategies. To do this, I have developed a novel knockin reporter allele, p16-LUC, which expresses firefly luciferase under control of the endogenous p16INK4a promoter. Importantly, my preliminary data show that induction of this allele correlates with cellular senescence in vitro and can be visualized in living animals. Using these mice I plan to address the following specific aims: 1) Characterize the p16- LUC allele under conditions relevant to the mammalian aging process, 2) Investigate the influence of diet and exercise on the induction of p16INK4a, 3) Determine the time- dependent and organ-specific effects of diet and exercise on p16INK4a promoter occupancy. PUBLIC HEALTH RELEVANCE: These studies will determine the potential of a new mouse model to predict how exercise and diet influence biological aging. In addition, we will gain insight into the processes that cause our bodies to age, helping us to develop new strategies that promote human health and longevity.

描述(申请人提供)：随着65岁以上美国人数量的增加，与年龄相关的疾病的发病率持续上升。因此，现在的研究重点是发现延长寿命的方法。虽然生物年龄的分子指示物很少，但我们和其他人最近已经表明，p16INK4a是哺乳动物衰老的一个强大而准确的标记。P16INK4a的诱导与啮齿动物的实际年龄直接相关，并可通过卡路里限制等抗衰老策略来减缓。此外，我们的初步数据显示，在健康受试者中，适度运动会降低p16INK4a的水平。尽管有这些数据，但改变生活方式促进长寿的机制在很大程度上仍然不清楚。在此，我将利用p16INK4a作为衰老生物标志物的独特性质来评估抗衰老策略的组织特异性。为了做到这一点，我开发了一个新的敲门报告等位基因p16-Luc，它在内源p16INK4a启动子的控制下表达萤火虫荧光素酶。重要的是，我的初步数据显示，该等位基因的诱导与体外细胞衰老有关，并且可以在活体动物中观察到。利用这些小鼠，我计划解决以下特定目标：1)在与哺乳动物衰老过程相关的条件下表征p16-Luc等位基因，2)调查饮食和运动对p16INK4a诱导的影响，3)确定饮食和运动对p16INK4a启动子占有率的时间依赖性和器官特异性影响。 公共卫生相关性：这些研究将确定一种新的小鼠模型预测运动和饮食如何影响生物衰老的潜力。此外，我们还将深入了解导致我们身体衰老的过程，帮助我们制定促进人类健康和长寿的新战略。