A Biochemical Approach to the Problem of Aging: "Megaproject" on Penetrating Ions (review)
An attempt is undertaken to decelerate aging of animals by antioxidant specifically addressed to mitochondria. To this end, a project has been established in which several research groups from Belozersky Institute of Physico-Chemical Biology and from some other Russian scientific institutes as well as two groups from USA and Sweden have been involved (sponsor, the "Mitotechnology" company). In this paper, I shall summarize the first results of the project and its probable perspectives. Within the framework of the project, antioxidants of a new type called SkQ have been syn-thesized. These substances are composed of (i) a chloroplast electron carrier plastoquinone (antioxidant moiety), (ii) a penetrating cation and (iii), a decane or pentane linker. Using a planar bilayer phospholipid membrane (BLM), we selected those SkQ derivatives which rapidly penetrate biomembranes, namely plastoquinonyl decyl triphenylphos-phonium (SkQl), plastoquinonyl decyl rhodamine 19 (SkQRl), and methylplastoquinonyl decyl triphenylphospho-nium (SkQ3). In isolated mitochondria these cationic quinones were tested for anti- and prooxidant activities. It was found that at micromolar concentrations, all of them, as well as their ubiquinone analog MitoQ, are very strong prooxidants. As to antioxidant activity, it is inherent in lower concentrations of SkQ and MitoQ. This activity increas-es in the range: MitoQ < SkQ3 < SkQRl = SkQl so the gap between anti- and prooxidant concentrations was small-est for MitoQ and largest for SkQl or SkQRl. It was shown that SkQl is rapidly reduced by Complex I and II of the mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. On the human fibroblasts and HeLa cells, it was revealed that extremely low concentrations of SkQl and SkQRl completely arrest H<sub>2</sub>0<sub>2</sub>-induced apoptosis (for SkQRl, <i>C</i><sub><i>1/2</i></sub><i> = </i>1 1O <sup>-12</sup> M). Higher SkQ amounts are required to block necrosis initiated by reactive oxygen species (ROS). In experiments on mice, we found that development of three types of progeria as well as normal aging are decelerated by SkQl. The effect is especially strong at early stages of aging. The same relationships are revealed in invertebrates (Drosophila and Daphnia were studied). In mammals, the effect of SkQ on aging is accompanied by inhibition of development of such diseases as osteoporosis, involution of thymus, cataract, retinopathy, etc. SkQl showed a strong therapeutic action upon some already developed retinopathies such as inherited retinal dysplasia. Among 66 animals (dogs, cats, and horses) who were blind due to a retinopathy, in 50 cases vision was recovered. In rabbits, experimental uveitis resulting in blindness was retarded and reversed by instillation of drops of 250 nM SkQl. Favorable effect was also achieved when experimental glaucoma was studied in rabbits. Moreover, it was found that pretreatment of rats with 0.2 nM SkQl significantly decreased the H<sub>2</sub>0<sub>2</sub>-induced arrhythmia of isolated heart. SkQl strongly reduced the area of injury in heart infarction or stroke and saved the life of rats suffering from kidney infarc-tion. In the p53<sup> -/_ </sup>mice, SkQl decreased the ROS level in the spleen cells and inhibited appearance of lymphomas, the main cause of the death of such animals. It is concluded that SkQ is promising as a potential drug to treat age-related diseases.