Genetic Influences on Age-Related Decline in Strength

遗传对年龄相关力量下降的影响

• 批准号: 6867836
• 负责人: Brock Allen Beamer
• 金额: $ 36.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867836
• 关键词: aging; body composition; clinical research; developmental genetics; frail elderly; functional /structural genomics; gene environment interaction; human subject; longitudinal human study; molecular pathology; muscle function; muscle metabolism; muscle strength; single nucleotide polymorphism; striated muscles

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.

骨骼肌质量和力量的下降会导致老年人功能能力的下降。事实上，肌肉无力是虚弱的多系统综合症的核心组成部分--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，由于这些变化，一些人在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，即这种变异性部分归因于遗传异质性和相关的基因-环境相互作用；即，有一些多态总是可以防止脆弱的发展，有些多态会加速脆弱的发展，有些多态只有在特定的荷尔蒙或营养环境中才会产生明显的影响。调节强度下降速度的基因变异将清楚地识别对强度下降至关重要的分子途径，这些途径可能对更普遍的脆弱发展，甚至对衰老过程本身都很重要。我们建议对强度随年龄下降的异质性的基因贡献者进行筛查。专家小组将根据流行病学研究中已知的强度下降预测因子(如IL6、DHEAS)对分子途径的贡献可能性对基因进行优先排序。将使用珠阵列技术对大约200个基因进行单倍型分析，以分析1500个SNPs。将对1,012名老年妇女的DNA进行基因分型，这些研究是专门为评估导致功能衰退和残疾的因素而设计的纵向研究(妇女健康和老龄化研究I和II)。单独或与血清生物标记物(如IL6受体基因X血清IL6)相互作用的与纵向强度下降速率相关的单个SNP或单倍型将在第二个老年人纵向队列中进行基因分型(心血管健康研究)。因此，被确认与强度下降相关的基因组区域将被测序，以确定与这些关联相关的特定变异。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，以及识别与年龄相关的身体成分变化、由此产生的虚弱，甚至衰老过程本身的基础研究的新靶点。