Gruber Jan, Schaffer Sebastian, Halliwell Barry
National University of Singapore, Department of Biochemistry, Centre for Life Sciences, 28 Medical Drive, 117456 Singapore.
Front Biosci. 2008 May 1;13:6554-79. doi: 10.2741/3174.
Understanding the molecular mechanisms underlying the ageing process may provide the best strategy for addressing the challenges posed by ageing populations worldwide. One theory proposing such molecular mechanisms was formulated 50 years ago. Harman et al. suggested that ageing might be mediated by macromolecular damage through reactions involving reactive oxygen species (ROS). Today, a version of the free radical theory of ageing, focusing on mitochondria as source as well as target of ROS, is one of the most popular theories of ageing. Here we critically review the status of key principles and concepts on which this theory is based. We find that the evidence to date shows that many of the original assumptions are questionable, while on some critical issues further refinements in techniques are required. Even so, it is becoming evident that mitochondria and mtDNA integrity may indeed be crucial determinants of organismal ageing. Implications for the prospect of successful interventions as well as evidence for and against efficacy of current therapeutic approaches are discussed.
了解衰老过程背后的分子机制可能是应对全球老龄化人口带来挑战的最佳策略。一个提出此类分子机制的理论是在50年前形成的。哈曼等人提出，衰老可能是由涉及活性氧（ROS）的反应导致的大分子损伤所介导的。如今，衰老自由基理论的一个版本，将线粒体视为ROS的来源和靶点，是最流行的衰老理论之一。在此，我们批判性地回顾了该理论所基于的关键原理和概念的现状。我们发现，迄今为止的证据表明，许多最初的假设存在疑问，而在一些关键问题上，需要进一步改进技术。即便如此，线粒体和线粒体DNA完整性确实可能是机体衰老的关键决定因素这一点正变得越来越明显。本文还讨论了成功干预前景的影响以及当前治疗方法有效性的支持和反对证据。
