Evolutionary Biochemistry and Redox Medicine, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany.
Geroscience. 2020 Jun;42(3):857-866. doi: 10.1007/s11357-019-00058-2. Epub 2019 Feb 27.
Modern geroscience is divided as regards the validity of the free radical theory of aging. Thermodynamic arguments and observations from comparative zoology support it, whereas results from experimental manipulations in representative animal species sometimes strongly contradict it. From a comparison of the multi-step aging process with a linear metabolic pathway (glycolysis), we here argue that the identification of the rate-limiting kinetic steps of the aging cascade is essential to understand the overall flux through the cascade, i.e., the rate of aging. Examining free radical reactions as a case in point, these reactions usually occur as chain reactions with three kinetically independent steps: initiation, propagation, and termination, each of which can be rate-limiting. Revisiting the major arguments in favor and against a role of free radicals in aging, we find that the majority of arguments in favor point to radical propagation as relevant and rate-limiting, whereas almost all arguments in disfavor are based on experimental manipulations of radical initiation or radical termination which turned out to be ineffective. We conclude that the overall lack of efficacy of antioxidant supplementation (which fosters termination) and antioxidant enzyme overexpression (which inhibits initiation) in longevity studies is attributable to the fact that initiation and termination are not the rate-limiting steps of the aging cascade. The biological and evolutionary plausibility of this interpretation is discussed. In summary, radical propagation is predicted to be rate-limiting for aging and should be explored in more detail.
现代衰老生物学在自由基衰老理论的有效性方面存在分歧。热力学论点和比较动物学的观察结果支持这一理论，而代表性动物物种的实验操作结果有时则强烈与之矛盾。从多步骤衰老过程与线性代谢途径（糖酵解）的比较来看，我们认为，确定衰老级联的限速动力学步骤对于理解整个级联的通量（即衰老速度）至关重要。以自由基反应为例，这些反应通常作为具有三个动力学独立步骤的链式反应发生：引发、传播和终止，每个步骤都可能是限速的。重新审视支持和反对自由基在衰老中起作用的主要论点，我们发现，大多数支持自由基传播的论点都认为自由基传播是相关的和限速的，而几乎所有反对的论点都是基于自由基引发或自由基终止的实验操作，这些操作被证明是无效的。我们得出结论，抗氧化剂补充（促进终止）和抗氧化酶过表达（抑制引发）在长寿研究中缺乏整体疗效，这归因于引发和终止不是衰老级联的限速步骤。还讨论了这种解释在生物学和进化上的合理性。总之，自由基传播预计对衰老具有限速作用，应该更详细地探讨。
