Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States.
Dornsife College of Letters, Arts, and Science, Department of Molecular and Computational Biology, University of Southern California, Los Angeles, United States.
Elife. 2022 Apr 26;11:e74308. doi: 10.7554/eLife.74308.
The influence of genetic variation on the aging process, including the incidence and severity of age-related diseases, is complex. Here, we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a predictive biomarker for age-related changes in muscle health by combining genetics and a gene-wide association scanning (GeneWAS) from older human participants of the US Health and Retirement Study (HRS). In a screen for mutations that activate oxidative stress responses, specifically in the muscle of , we identified 96 independent genetic mutants harboring loss-of-function alleles of , exclusively. Each of these genetic mutations mapped to the ALH-6 polypeptide and led to the age-dependent loss of muscle health. Intriguingly, genetic variants in show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.
遗传变异对衰老过程的影响，包括与年龄相关疾病的发病率和严重程度，是复杂的。在这里，我们通过结合美国健康与退休研究（HRS）中老年人的遗传学和全基因组关联扫描（GeneWAS），将进化上保守的线粒体酶 ALH-6/ALDH4A1 定义为与肌肉健康相关的衰老变化的预测性生物标志物。在筛选专门针对肌肉中氧化应激反应的激活的突变时，我们在 中鉴定了 96 个独立的遗传突变体，它们仅携带 的功能丧失等位基因。这些遗传突变中的每一个都映射到 ALH-6 多肽上，并导致肌肉健康随年龄的依赖性丧失。有趣的是， 中的遗传变异与人类与年龄相关的肌肉功能相关。总之，我们的工作揭示了线粒体 作为影响跨物种正常肌肉衰老的关键组成部分，以及预测肌肉健康寿命的生物标志物。
