Aging and Immunity Laboratory, Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea.
Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea; Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea.
Exp Gerontol. 2023 Oct 1;181:112269. doi: 10.1016/j.exger.2023.112269. Epub 2023 Sep 1.
Ageing alters the ECM, leading to mitochondrial dysfunction and oxidative stress, which triggers an inflammatory response that exacerbates with age. Age-related changes impact satellite cells, affecting muscle regeneration, and the balance of proteins. Furthermore, ageing causes a decline in NAD levels, and alterations in fat metabolism that impact our health. These various metabolic issues become intricately intertwined with ageing, leading to a variety of individual-level diseases and profoundly affecting individuals' healthspan. Therefore, we hypothesize that vutiglabridin capable of alleviating these metabolic abnormalities will be able to ameliorate many of the problems associated with ageing.
The efficacy of vutiglabridin, which alleviates metabolic issues by enhancing mitochondrial function, was assessed in aged mice treated with vutiglabridin and compared to untreated elderly mice. On young mice, vutiglabridin-treated aged mice, and non-treated aged mice, the Senescence-associated beta-galactosidase staining and q-PCR for ageing marker genes were carried out. Bulk RNA-seq was carried out on GA muscle, eWAT, and liver from each group of mice to compare differences in gene expression in various gene pathways. Blood from each group of mice was used to compare and analyze the ageing lipid profile.
SA-β-gal staining of eWAT, liver, kidney, and spleen of ageing mice showed that vutiglabridin had anti-ageing effects compared to the control group, and q-PCR of ageing marker genes including Cdkn1a and Cdkn2a in each tissue showed that vutiglabridin reduced the ageing process. In aged mice treated with vutiglabridin, GA muscle showed improved homeostasis compared to controls, eWAT showed restored insulin sensitivity and prevented FALC-induced inflammation, and liver showed reduced inflammation levels due to prevented TLO formation, improved mitochondrial complex I assembly, resulting in reduced ROS formation. Furthermore, blood lipid analysis revealed that ageing-related lipid profile was relieved in ageing mice treated with vutiglabridin versus the control group.
Vutiglabridin slows metabolic ageing mechanisms such as decreased insulin sensitivity, increased inflammation, and altered NAD metabolism in adipose tissue in mice experiments, while also retaining muscle homeostasis, which is deteriorated with age. It also improves the lipid profile in the blood and restores mitochondrial function in the liver to reduce ROS generation.
衰老改变细胞外基质，导致线粒体功能障碍和氧化应激，从而引发炎症反应，随着年龄的增长而加剧。与年龄相关的变化会影响卫星细胞，影响肌肉再生和蛋白质平衡。此外，衰老会导致 NAD 水平下降，脂肪代谢改变，从而影响我们的健康。这些各种代谢问题与衰老错综复杂地交织在一起，导致各种个体疾病，并深刻影响个体的健康寿命。因此，我们假设 vutiglabridin 能够缓解这些代谢异常，将能够改善许多与衰老相关的问题。
通过增强线粒体功能来缓解代谢问题的 vutiglabridin 的功效，在接受 vutiglabridin 治疗的老年小鼠和未接受治疗的老年小鼠中进行了评估。对年轻小鼠、vutiglabridin 治疗的老年小鼠和未治疗的老年小鼠进行衰老相关β-半乳糖苷酶染色和衰老标志物基因的 q-PCR。对每组小鼠的 GA 肌肉、eWAT 和肝脏进行 bulk RNA-seq，以比较不同基因通路中基因表达的差异。比较和分析每组小鼠血液中的衰老脂质谱。
衰老小鼠的 eWAT、肝脏、肾脏和脾脏的 SA-β-半乳糖苷染色显示，与对照组相比，vutiglabridin 具有抗衰老作用，并且每个组织中的衰老标志物基因（包括 Cdkn1a 和 Cdkn2a）的 q-PCR 显示，vutiglabridin 减少了衰老过程。在接受 vutiglabridin 治疗的老年小鼠中，GA 肌肉的稳态较对照组得到改善，eWAT 显示胰岛素敏感性得到恢复，并防止了 FALC 诱导的炎症，肝脏由于 TLO 形成减少、线粒体复合物 I 组装改善而导致炎症水平降低，导致 ROS 形成减少。此外，血液脂质分析显示，与对照组相比，衰老小鼠用 vutiglabridin 治疗可缓解与衰老相关的脂质谱。
vutiglabridin 在小鼠实验中减缓了代谢衰老机制，如胰岛素敏感性降低、炎症增加和脂肪组织中 NAD 代谢改变，同时保持肌肉稳态，而肌肉稳态随年龄增长而恶化。它还改善了血液中的脂质谱，并恢复了肝脏中的线粒体功能，以减少 ROS 的产生。
