Geriatric Unit, Graduate School of Medicine, Kyoto University, Sakyo-ku, 606-8507 Kyoto, Japan.
G0 Cell Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, 904-0495 Okinawa, Japan.
Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9483-9489. doi: 10.1073/pnas.1920795117. Epub 2020 Apr 15.
As human society ages globally, age-related disorders are becoming increasingly common. Due to decreasing physiological reserves and increasing organ system dysfunction associated with age, frailty affects many elderly people, compromising their ability to cope with acute stressors. Frail elderly people commonly manifest complex clinical symptoms, including cognitive dysfunction, hypomobility, and impaired daily activity, the metabolic basis of which remains poorly understood. We applied untargeted, comprehensive LC-MS metabolomic analysis to human blood from 19 frail and nonfrail elderly patients who were clinically evaluated using the Edmonton Frail Scale, the MoCA-J for cognition, and the TUG for mobility. Among 131 metabolites assayed, we identified 22 markers for frailty, cognition, and hypomobility, most of which were abundant in blood. Frailty markers included 5 of 6 markers specifically related to cognition and 6 of 12 markers associated with hypomobility. These overlapping sets of markers included metabolites related to antioxidation, muscle or nitrogen metabolism, and amino acids, most of which are decreased in frail elderly people. Five frailty-related metabolites that decreased-1,5-anhydroglucitol, acetyl-carnosine, ophthalmic acid, leucine, and isoleucine-have been previously reported as markers of aging, providing a metabolic link between human aging and frailty. Our findings clearly indicate that metabolite profiles efficiently distinguish frailty from nonfrailty. Importantly, the antioxidant ergothioneine, which decreases in frailty, is neuroprotective. Oxidative stress resulting from diminished antioxidant levels could be a key vulnerability for the pathogenesis of frailty, exacerbating illnesses related to human aging.
随着全球人口老龄化，与年龄相关的疾病越来越普遍。由于与年龄相关的生理储备减少和器官系统功能障碍增加，虚弱影响了许多老年人，使他们无法应对急性应激源。虚弱的老年人通常表现出复杂的临床症状，包括认知功能障碍、活动减少和日常活动能力受损，其代谢基础仍知之甚少。我们应用非靶向、全面的 LC-MS 代谢组学分析方法，对 19 名虚弱和非虚弱的老年患者的人血进行了分析，这些患者通过埃德蒙顿虚弱量表、MoCA-J 认知测试和 TUG 移动性测试进行了临床评估。在测定的 131 种代谢物中，我们确定了 22 种与虚弱、认知和活动减少相关的标志物，其中大多数在血液中含量丰富。虚弱标志物包括与认知相关的 6 个标志物中的 5 个和与活动减少相关的 12 个标志物中的 6 个。这些重叠的标志物集包括与抗氧化、肌肉或氮代谢和氨基酸相关的代谢物，其中大多数在虚弱的老年人中减少。5 种与虚弱相关的代谢物（1,5-脱水葡萄糖醇、乙酰肉碱、眼氨酸、亮氨酸和异亮氨酸）以前被报道为衰老的标志物，为人类衰老和虚弱之间的代谢联系提供了证据。我们的研究结果清楚地表明，代谢物谱可以有效地将虚弱与非虚弱区分开来。重要的是，抗氧化剂麦角硫因在虚弱时减少，具有神经保护作用。抗氧化剂水平降低导致的氧化应激可能是虚弱发病机制的一个关键弱点，加剧了与人类衰老相关的疾病。
