Genetic Influences on Age-Related Decline in Strength

骨骼肌质量和力量的下降导致老年人功能能力的下降。事实上，肌肉无力是多系统虚弱综合征的核心组成部分，是残疾、疾病甚至死亡的有力预示。虽然这种下降是普遍发生的，但发病的年龄和进展的速度却各不相同，有些人在70多岁时变得虚弱和残疾，但有些人在10岁时仍然相当健康。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；也就是说，有一些多态性总是会防止脆弱的发展，有些会加速它，有些只在某种激素或营养环境中才会有明显的影响。调节力量下降速度的基因变异将清楚地确定对这种下降很重要的分子途径，这些途径可能对更普遍的脆弱的发展，甚至对衰老过程本身很重要。我们提出筛选遗传因素的异质性在强度下降的速度随年龄增长。专家小组将根据流行病学研究中已知强度下降预测因子的分子途径的可能性对基因进行优先排序（例如il - 6， DHEAS）。单倍型分析将对大约200个基因进行，使用头阵列技术检测1500个snp。将对1012名参与纵向研究的老年妇女的DNA进行基因分型，这些纵向研究专门用于评估导致功能衰退和残疾的因素（妇女健康与老龄化研究I和II）。与强度纵向下降率相关的单个snp或单倍型，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，将在老年人的第二个纵向队列中进行基因分型（心血管健康研究）。因此，将对证实与强度下降相关的基因组区域进行测序，以确定导致这种关联的特定变异。识别变异预测力量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成分变化，由此导致的虚弱，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.