Recently we developed a concept assuming that senescence is programmed by genome, being the last step of ontogenesis. It was also suggested that senescence was invented by biological evolution to accelerate this evolution [1 - 3]. A consequence of such kind of reasoning consists in that for humans senescence should be regarded as an atavism since humans do not rely on their evolution which is too slow. If senescence is programmed, it might be prevented by inhibition of this program just as inhibition of the programmed cell death (apoptosis) is shown to prevent apoptosis [1]. There are numerous indications that senescence program declines physiological functions by means of toxic
reactive oxygen species (ROS) produced in mitochondria [1, 2, 4]. Hence, one may hope that mitochondrial-targeted antioxidants might be inhibitors of the senescence program.
To study such a possibility, a project has been established with participation of several research groups from Russia, Sweden and USA [4, 5]. A new type of compounds (SkQs) composed of plastoquinone (an antioxidant moiety), a penetrating cation with delocalized charge and a decane or pentane linker has been synthesized [4 - 6] (Fig.1).

 

Fig. 1 Structures of SkQ1 (left) and C12TPP (right)

The working hypothesis was that such positively charged compounds will be specifically targeted to the 2 nm layer of the inner mitochondrial membrane, being electrophoretically accumulated inside mitochondria, the only negatively charged compartment of the living cell [7 – 9]. In this case, penetrating cation moiety of SkQ could operate as “electric locomotive” of nanometer size, transporting antioxidant plastoquinone to mitochondria.

 

Using planar bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest permeability, namely plastoquinonyl decyltriphenylphosphonium (SkQ1), plastoquinonyl decylrhodamine 19 (SkQR1), and methylplastoquinonyl decyltriphenylphosphonium (SkQ3) [4, 6]. Anti- and prooxidant properties of these substances and also of ubiquinonyl decyltriphenylphosphonium (MitoQ) were tested in aqueous solutions, detergent micelles, liposomes, BLM, isolated mitochondria, cell cultures, and organisms [4, 6, 10 – 12]. In mitochondria, micromolar cationic quinone derivatives were found to be prooxidants, but at lower (nanomolar) concentrations they displayed antioxidant activity that decreases in the series SkQ1 = SkQR1 > SkQ3 > MitoQ. SkQ1 was reduced by mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Under condition of oxidative stress, SkQ1 specifically prevented oxidation of mitochondrial cardiolipin. In cell cultures, SkQR1, a fluorescent SkQ derivative, stained only one type of organelles, namely
mitochondria. Extremely low concentrations of SkQ1 or SkQR1 arrested H2O2-induced apoptosis in human fibroblasts and HeLa cells. Higher concentrations of SkQ were required to block necrosis initiated by ROS [4, 6]. In the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, drosophila, the fish Nothobranchius fuzreri and mice, SkQ1 prolonged median lifespan. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, anemia, disappearance of estrous cycles in females and libido in males, torpor, hypothermia, peroxidation of lipids and proteins, etc [4, 13, 14]. SkQ1 excluded infection diseases from the list of death reasons. This was most probably due to prevention of the age-reasoned decline of immunity (in particular, involution of thymus and a decrease in area occupied by spleen follicles [4, 14]). Moreover, SkQ1 manifested a strong therapeutic action on already pronounced cataract as well as retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Instillation of SkQ1-containing drops prevented the loss of sight in rabbits with experimental uveitis and restored vision to animals that had already become blind. A favorable effect of the same drops was also achieved in experimental glaucoma in rabbits [4, 15]. Moreover, the SkQ1 pretreatment of rats significantly
decreased the H2O2- or ischemia-induced arrhythmia of the isolated heart. SkQs strongly reduced the damaged area in experimental myocardial infarction or stroke and prevented the death of animals from kidney ischemia [4, 16, 17]. In p53–/– mice, 5 nmol SkQ1/kg x day decreased the ROS level in the spleen and inhibited appearance of lymphomas to the same degree as million-fold higher concentration of conventional antioxidant N-acetylcysteine [4, 18].

 

Quite recently, it was shown in our group that SkQ1 and C12TPP (an SkQ analog lacking plastoquinone moiety, see Fig.1) can operate as nanocarriers of fatty acid anions across model and natural membranes [19, 20]. In this way, they catalyze circulating of fatty acids in mitochondria (Fig.2), resulting in mild uncoupling of respiration and energy accumulation, decrease in mitochondrial membrane potential and, hence, in the ROS production. This may mimic caloric restriction of the food, which is known to prolong the lifespan of various organisms (from yeast to mammals). Thus, SkQs look promising as potential tools for treatment of senescence and age-related diseases (for reviews, see [4, 5, 21, 22]).

 

Fig. 2 Fatty acid cycling mediated by C12TPP.

 

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