Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.

衰老是一种复杂的现象，涉及多个生理系统的功能下降。我们对四种不同物种的骨骼肌进行了比较分析，即小鼠，大鼠，恒河猴和人类，它们在生命的三个不同代表阶段（年幼，中年和年老）确定了调节功能和健康期的途径。基因表达谱分析和计算分析表明，从小鼠到人类的途径复杂性在增加，并且随着哺乳动物的年龄增长，所有物种中的途径主要都呈上调状态。响应衰老，这四个物种之间共有两个下调的途径，即电子传输链和氧化磷酸化。定量PCR，生化分析，线粒体DNA测量，电子显微镜显示，猴子和人类的线粒体含量随年龄的增长而减少，而氧化磷酸化复合物的减少。线粒体生物发生过程中关键蛋白质的蛋白质印迹分析发现（i）老年骨骼肌发生线粒体融合失衡;（ii）线粒体并未受到明显影响，可能导致观察到的异常大，受损的线粒体随着年龄的积累。选择性转录本表达分析发现，骨骼炎性特征随年龄的增长而差异增加，但在人类中最为明显，而氧化应激（由蛋白羰基加合物和4-羟基壬烯评估）在所有物种中均很普遍。表达研究还发现，随着年龄的增长，不同物种之间的营养感应途径存在独特的失调。保守途径的鉴定表明了健康和寿命固有的共同分子机制，而对物种特异性途径的认识强调了人类研究对于设计最佳治疗方式以减缓衰老过程的重要性。