Abstract
Testing the predictions of the Mitochondrial Free Radical Theory of Ageing (MFRTA) has provided a deep understanding of the role of reactive oxygen species (ROS) and mitochondria in the aging process. However those data, which support MFRTA are in the majority correlative (e.g. increasing oxidative damage with age). In contrast the majority of direct experimental data contradict MFRTA (e.g. changes in ROS levels do not alter longevity as expected). Unfortunately, in the past, ROS measurements have mainly been performed using isolated mitochondria, a method which is prone to experimental artifacts and does not reflect the complexity of the in vivo process. New technology to study different ROS (e.g. superoxide or hydrogen peroxide) in vivo is now available; these new methods combined with state-of-the-art genetic engineering technology will allow a deeper interrogation of, where, when and how free radicals affect aging and pathological processes. In fact data that combine these new approaches, indicate that boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan. In this review, I discuss the latest literature focused on the role of mitochondrial ROS in aging, and how these new discoveries are helping to better understand the role of mitochondria in health and disease. This article is part of a Special Issue entitled ‘EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2–6, 2016’, edited by Prof. Paolo Bernardi.
Highlights
The Free Radical Theory of Ageing, later updated to the Mitochondrial Free Radical Theory of Ageing (MFRTA) was proposed by Denham Harman in 1956 and 1972 respectively [1,2]
The efforts to test MFRTA have been instrumental in gaining a better understanding of the aging process, our knowledge of how free radicals participate in cellular physiology has been extended far beyond the aging field
Primary support for MFRTA comes from descriptive studies which established that reactive oxygen species (ROS) production and oxidative damage accumulate with age [3–6], and from correlative studies showing that ROS levels correlate with lifespan in long-lived animals [7–9] or individuals [10–13]
Summary
The Free Radical Theory of Ageing, later updated to the Mitochondrial Free Radical Theory of Ageing (MFRTA) was proposed by Denham Harman in 1956 and 1972 respectively [1,2]. Primary support for MFRTA comes from descriptive studies which established that ROS production and oxidative damage accumulate with age [3–6], and from correlative studies showing that ROS levels correlate with lifespan in long-lived animals [7–9] or individuals [10–13]. As mentioned previously, ROS levels have been shown repeatedly to be altered in aging and age-related diseases. It has recently been shown that lifespan of the longlived clk-1 mutant worm is further extended by increasing mitochondrial ROS levels through knock-out of sod2 [28]. Increasing cytosolic ROS levels, by knocking out sod and sod, shortened lifespan of this long-lived mutant. This indicates that ROS can have opposing effects on longevity, depending on whether they are produced within or outside of mitochondria. This highlights the importance of understanding where ROS are generated
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