Mitochondrial DNA Variation in Human Energy Expenditure and Metabolic Rate

描述(申请人提供)：较高的自由生活活动能量消耗与较低的冠心病、癌症发病率、跌倒和老年人死亡率密切相关。然而，目前尚不清楚活动能量消耗如何保护老年人免受身体残疾和过早死亡的影响。近年来，线粒体功能对癌症、糖尿病和神经变性等与年龄相关的疾病进展速度的重要性日益明显。然而，目前人们对线粒体DNA突变在人类生物能量学中的作用知之甚少。我们的主要目的是评估线粒体DNA多态和异质性与老年人活动能量消耗和静息代谢率的关系。我们将通过对健康、老龄化和身体成分(Health ABC)研究队列中的健康样本进行测试来实现我们的主要目标。1998-1999年对302名高功能社区老年人(70-82岁)的活动能量消耗和静息代谢率进行了测量。我们将使用最近开发的Affymetrix线粒体重测序阵列v2.0(MitoChip)对200名研究参与者的整个mtDNA基因组进行测序，这些参与者来自自由生活活动能量消耗的最高和最低三分位数(分别为770kcal/d和521kcal/d)。这项研究的结果可能直接将mtDNA突变与老年人的能量消耗和代谢率联系起来，并提供了一种特定的mtDNA突变事件导致生物能源性下降和随后死亡的机制。我们的研究结果可能具有深远的生物学和临床意义。识别影响能量消耗和代谢率的基因变异最终可能导致干预措施延长人类多产和健康的寿命。公共卫生相关性：我们的主要目的是评估线粒体DNA多态和异质性与老年人活动能量消耗和静息代谢率的关系。我们将通过对健康、老龄化和身体成分(Health ABC)研究队列中的健康样本进行测试来实现我们的主要目标。我们将使用最近开发的Affymetrix线粒体重测序阵列v2.0(MitoChip)对200名研究参与者的整个mtDNA基因组进行测序，这些参与者来自自由生活活动能量消耗的最高和最低三分位数。这项研究的结果可能直接将mtDNA突变与老年人的能量消耗和代谢率联系起来，并提供了一种特定的mtDNA突变事件导致生物能源性下降和随后死亡的机制。

DESCRIPTION (provided by applicant): Higher free-living activity energy expenditure is strongly associated with lower risks of coronary heart disease, cancer incidence, falls, and mortality among older adults. It is unknown, however, how activity energy expenditure can protect older adults from physical disability and premature mortality. The importance of mitochondrial function to the rate of progression of age-related diseases such as cancer, diabetes, and neurodegeneration has become increasingly apparent in recent years. Yet little is currently known about the role of mtDNA mutations in human bioenergetics. Our primary aim is to assess the association of mtDNA polymorphisms and heteroplasmy with active energy expenditure and resting metabolic rate in the elderly. We will carry out our primary aim in a test of healthy samples from the Health, Aging and Body Composition (Health ABC) Study cohort. Active energy expenditure and resting metabolic rate were measured in 1998-1999 in 302 high-functioning, community-dwelling older adults (aged 70-82 years). We will use the recently developed Affymetrix Mitochondrial Resequencing Array v2.0 (MitoChip) to sequence the entire mtDNA genome of 200 study participants from the highest and lowest tertiles of free-living activity energy expenditure (>770 kcal/d and <521 kcal/d, respectively). The results of this study may directly link mtDNA mutations with energy expenditure and metabolic rate in the elderly and provide a mechanism by which specific mtDNA mutational events contribute to bioenergenic decline and subsequent mortality. The results of our study may have profound biological and clinical significance. Identifying genetic variants that influence energy expenditure and metabolic rate could eventually lead to interventions that prolong the productive and healthy years of human life. PUBLIC HEALTH RELEVANCE: Our primary aim is to assess the association of mtDNA polymorphisms and heteroplasmy with active energy expenditure and resting metabolic rate in the elderly. We will carry out our primary aim in a test of healthy samples from the Health, Aging and Body Composition (Health ABC) Study cohort. We will use the recently developed Affymetrix Mitochondrial Resequencing Array v2.0 (MitoChip) to sequence the entire mtDNA genome of 200 study participants from the highest and lowest tertiles of free- living activity energy expenditure. The results of this study may directly link mtDNA mutations with energy expenditure and metabolic rate in the elderly and provide a mechanism by which specific mtDNA mutational events contribute to bioenergenic decline and subsequent mortality.