Genetic Influences on Age-Related Decline in Strength

骨骼肌质量和强度的下降导致老年人功能能力的下降。事实上，肌肉无力是多系统综合征的核心组成部分--这是残疾、疾病甚至死亡的有力预测因素。虽然这种下降是普遍发生的，但发病年龄和进展速度差异很大，有些人在70多岁时因这些变化而变得虚弱和残疾，但有些人在10岁时仍然非常健壮。现在有证据支持我们的假设，即这种变异性部分是由于遗传异质性和相关的基因-环境相互作用造成的;也就是说，有些多态性总是能防止虚弱的发展，有些会加速虚弱的发展，有些只在某种激素或营养环境中才有明显的影响。调节力量下降速度的基因变异将清楚地识别出对力量下降重要的分子路径，这些路径可能对更普遍的虚弱发展，甚至对衰老过程本身都很重要。我们提出了一个屏幕的遗传贡献者的异质性的下降速度在强度与老化。专家小组将根据流行病学研究中已知强度下降预测因子（例如IL 6、DHEAS）对分子途径的贡献可能性对基因进行优先排序。将对大约200个基因进行单倍型分析，使用微珠阵列技术测定1，500个SNP。将对1,012名老年妇女的DNA进行基因分型，这些妇女是专门设计来评估功能下降和残疾的纵向研究（妇女健康和老龄化研究I和II）。将在老年人的第二个纵向队列中对与力量纵向下降速率相关的单个SNP或单倍型进行基因分型（单独或与血清生物标志物（例如IL 6受体基因X血清IL 6）相互作用）（心血管健康研究）。将对由此证实与强度下降相关的基因组区域进行测序，以鉴定解释相关性的特定变体。确定变异预测强度下降的分子途径将有助于临床和研究工作的风险分层，新疗法的开发，以及确定与年龄相关的身体组成变化，由此产生的虚弱甚至衰老过程本身的基础研究的新目标。

Declines in the mass and strength of skeletal muscle lead to decrements in functional abilities of older adults. In fact, muscle weakness is the central component of the multisystem syndrome of frailty--a strong predictor of disability, illness and even death. While this decline is universal in occurrence, the age of onset and speed of progression are quite variable, with some persons becoming frail and disabled in their 70s as a result of these changes, yet some remaining quite robust into their 10th decade. There is now evidence to support our hypothesis that such variability is due, in part, to genetic heterogeneity and to associated gene-environment interactions; i.e. there are polymorphisms that will most always protect against development of frailty, some that will hasten it, and some that will have effects apparent only in a certain hormonal or nutritional milieu. Gene variants that modulate the rate of decline in strength will clearly identify molecular paths important to that decline, paths perhaps important to development of frailty more generally, or even to the aging process itself. We propose a screen for genetic contributors to heterogeneity in the rate of decline in strength with aging. An expert panel will prioritize genes based upon likelihood of contribution to the molecular pathway of a known predictor of decline in strength in epidemiologic studies (e.g. IL6, DHEAS). Haplotype analysis will be performed on approximately 200 genes, using bead array technology to assay 1,500 SNPs. Genotyping will be performed on DNA of 1,012 older women of longitudinal studies specifically designed to assess contributors to functional decline and disability (Women's Health and Aging Studies I and II). Individual SNPs or haplotypes that associate with longitudinal rate of decline in strength, individually or in interaction with a serum biomarker (e.g. IL6 receptor gene X serum IL6), will be genotyped in a second longitudinal cohort of older adults (Cardiovascular Health Study). Genomic regions thereby confirmed to associate with decline in strength will be sequenced to identify specific variants accounting for the associations. Identifying molecular pathways in which variation predicts declines in strength will aid in risk stratification for clinical and research endeavors, development of new therapies, and identification of new targets for basic research on age-related changes in body composition, resultant frailty, and even the aging process itself.