Sanz Alberto, Stefanatos Rhoda K A
Mitochondrial Gene Expression and Disease Group, Institute of Medical Technology, University of Tampere, Biokatu 6, FI-33520 Tampere, Finland.
Curr Aging Sci. 2008 Mar;1(1):10-21. doi: 10.2174/1874609810801010010.
The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA. At its most orthodox MFRTA proposes that these free radicals damage mitochondrial DNA (mtDNA) and in turn provoke mutations that alter mitochondrial function (e.g. ATP production). According to this, oxidative damage to mtDNA negatively correlates with maximum life span in mammals. However, in contrast to MFRTA predictions, high levels of oxidative damage in mtDNA do not decrease longevity in mice. Moreover, mice with alterations in polymerase gamma (the mitochondrial DNA polymerase) accumulate 500 times higher levels of point mutations in mtDNA without suffering from accelerated aging. Dietary restriction (DR) is the only non-genetic treatment that clearly increases mean and maximum life span. According to MFRTA caloric restricted animals produce fewer mitochondrial reactive oxygen species (mtROS). However, DR alters more than free radical production (e.g. it decreases insulin signalling) and therefore the increase in longevity cannot be exclusively attributed to a decrease in mtROS generation. Thus, moderate exercise produces similar changes in free radical production and oxidative damage without increasing maximum life span. In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.
线粒体衰老自由基理论（MFRTA）提出，正常新陈代谢过程中产生的线粒体自由基会造成氧化损伤。根据MFRTA，这种氧化损伤的积累是衰老过程的主要驱动力。尽管该理论被广泛接受，但仍未得到证实，因为支持它的证据大多只是相关性的。例如，长寿动物产生的自由基较少，其组织中的氧化损伤水平也较低。然而，这并不能证明自由基的产生决定寿命。事实上，最长寿啮齿动物——裸鼹鼠——会产生大量自由基，其蛋白质、脂质和DNA中的氧化损伤水平也很高。在最正统的MFRTA观点中，这些自由基会破坏线粒体DNA（mtDNA），进而引发改变线粒体功能（如ATP生成）的突变。据此，mtDNA的氧化损伤与哺乳动物的最大寿命呈负相关。然而，与MFRTA的预测相反，mtDNA中的高水平氧化损伤并不会缩短小鼠的寿命。此外，线粒体DNA聚合酶γ发生改变的小鼠，其mtDNA中的点突变水平会高出500倍，但并未加速衰老。饮食限制（DR）是唯一能显著延长平均寿命和最大寿命的非基因治疗方法。根据MFRTA，热量限制的动物产生的线粒体活性氧（mtROS）较少。然而，DR改变的不仅仅是自由基的产生（例如它会降低胰岛素信号传导），因此寿命的延长不能完全归因于mtROS生成的减少。因此，适度运动在自由基产生和氧化损伤方面产生了类似的变化，但并未延长最大寿命。总之，关于自由基在寿命控制中作用的现有数据相互矛盾，无法证明MFRTA。事实上，检验该理论的唯一方法是在不改变其他生理参数（如胰岛素信号传导）的情况下，特异性地减少线粒体自由基的产生。如果MFRTA是正确的，那么产生较少mtROS的动物必须比其实验对照组活得长得多。
