Distinct designer diamines promote mitophagy, and thereby enhance healthspan in <i>C. elegans</i> and protect human cells against oxidative damage

Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population. Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in <i>C. elegans</i>. Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.

线粒体自噬（mitophagy）功能受损是阿尔茨海默病、帕金森病以及肌肉减少症等多种衰老相关疾病的核心致病事件。因此，增强线粒体自噬——即清除受损线粒体并以新生线粒体取而代之的过程——是预防老年人群多发慢性病进展的新兴策略。本研究以已知的线粒体自噬促进剂亚精胺（spermidine, Spd）为分子骨架，设计并测试了一系列结构相关的化合物家族。其中一款原型化合物1,8-二氨基辛烷（VL-004）在诱导线粒体自噬与对抗氧化应激的能力上优于亚精胺。VL-004的活性由经典衰老基因介导，并可延长秀丽隐杆线虫（C. elegans）的寿命与健康寿命。此外，该化合物可在啮齿类动物与人类细胞中增强线粒体自噬并对抗氧化损伤。初步的结构表征揭示了可优化化合物生物活性的简易设计规则，为开发新一代有望促进健康衰老的药物开辟了全新路径。

搜集汇总

背景与挑战

背景概述

该数据集围绕新型设计的二胺化合物VL-004展开研究，重点探讨其如何促进线粒体自噬，从而延长秀丽隐杆线虫的健康寿命并保护人类细胞免受氧化损伤。数据集包含实验数据和图表文件，支持研究结论的验证，涉及衰老、线粒体自噬和抗氧化应激等关键主题，适用于生物化学和医学领域的分析。