I.M. Sechenov First Moscow State Medical University (Sechenov University), 8 Trubetskaya Street, Moscow, 119991, Russia.
N.I. Pirogov Russian National Research Medical University, 1 Ostrovityanov Street, Moscow, 117997, Russia.
Oxid Med Cell Longev. 2019 Aug 14;2019:3085756. doi: 10.1155/2019/3085756. eCollection 2019.
Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging. Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF-B, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases. The accumulation of ROS under oxidative stress conditions results in the induction of lipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivatives such as glyoxal, methylglyoxal (MG), malonic dialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE) giving rise to advanced lipoxidation and glycation end products (ALEs and AGEs, respectively). Both ALEs and AGEs play key roles in cellular response to oxidative stress stimuli through the regulation of a variety of cell signaling pathways. However, elevated ALE and AGE production leads to protein cross-linking and aggregation resulting in an alteration in cell signaling and functioning which causes cell damage and death. This is implicated in aging and various age-related chronic pathologies such as inflammation, neurodegenerative diseases, atherosclerosis, and vascular complications of diabetes mellitus. In the present review, we discuss experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions. We focused on the implications of ALEs/AGEs in aging and age-related diseases to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.
氧化应激是生物有氧呼吸过程中氧气利用的结果，表现为活性氧（ROS）生成与内源性抗氧化系统（AOS）解毒能力之间失衡的持续状态。氧化应激理论在许多动物研究中得到证实，这些研究表明，维持细胞内环境平衡和生物分子的稳定性和完整性对于细胞的长寿和成功衰老至关重要。在线粒体功能障碍、蛋白质稳态（蛋白质组学）网络受损、转录因子（如 Nrf2 和 NF-B）活性改变、以及包括分子伴侣、泛素-蛋白酶体系统（UPS）和自噬/溶酶体途径在内的蛋白质质量控制机制紊乱等方面，在衰老和与年龄相关的慢性疾病中都有观察到。在氧化应激条件下 ROS 的积累导致脂质过氧化和糖基化反应的诱导，从而导致内源性反应性醛类及其衍生物（如乙二醛、甲基乙二醛（MG）、丙二醛（MDA）和 4-羟基-2-壬烯醛（HNE））的产生增加，从而导致晚期脂质过氧化和糖化终产物（分别为 ALE 和 AGE）的产生增加。ALE 和 AGE 都通过调节多种细胞信号通路，在细胞对氧化应激刺激的反应中发挥关键作用。然而，ALE 和 AGE 产量的增加会导致蛋白质交联和聚集，从而改变细胞信号转导和功能，导致细胞损伤和死亡。这与衰老和各种与年龄相关的慢性病理有关，如炎症、神经退行性疾病、动脉粥样硬化和糖尿病血管并发症。在本综述中，我们讨论了证明在氧化应激条件下 AGE/ALE 积累导致细胞功能受损的实验数据。我们重点讨论了 ALEs/AGEs 在衰老和与年龄相关疾病中的意义，以证明鉴定涉及疾病起始和进展的细胞功能障碍可以作为发现相关治疗药物的基础。
