SkQ1 as a Tool for Controlling Accelerated Senescence Program: Experiments with OXYS Rats.

According to the concept suggested by V. P. Skulachev and co-authors, aging of living organisms can be considered as a special case of programmed death of an organism - phenoptosis, and mitochondrial antioxidant SkQ1 is capable of inhibiting both acute and chronic phenoptosis (aging). The authors of the concept associate effects of SkQ1 with suppression of the enhanced generation of ROS in mitochondria. Numerous studies have confirmed the ability of SkQ1 to inhibit manifestations of the "healthy", or physiological, aging. According to the results of our studies, SkQ1 is especially effective in suppressing the program of genetically determined accelerated senescence in OXYS rats, which appears as an early development of a complex of age-related diseases: cataracts, retinopathy (similar to the age-related macular degeneration in humans), osteoporosis, and signs of Alzheimer's disease. Accelerated senescence in OXYS rats is associated with mitochondrial dysfunction, but no direct associations with oxidative stress have been identified. Nevertheless, SkQ1 is able to prevent and/or suppress development of all manifestations of accelerated senescence in OXYS rats. Its effects are due to impact on the activity of many signaling pathways and processes, but first of all they are associated with restoration of the structural and functional parameters of mitochondria. It could be suggested that the use of SkQ1 could represent a promising strategy in prevention of accelerated phenoptosis - early development of a complex of age-related diseases (multimorbidity) in people predisposed to it.

Ameliorative effects of SkQ1 eye drops on cataractogenesis in senescence-accelerated OXYS rats.

BACKGROUND: Antioxidant supplements have been suggested as a strategy to decrease the risk of age-related cataract, but there is no evidence that antioxidants can reduce the signs of the disease. Recently, we showed that the mitochondrial antioxidant SkQ1 can partially reverse cataract signs in senescence-accelerated OXYS rats. The aim of the present study was the histomorphological examination of the influence of SkQ1 eye drops on the cataract development in OXYS rats. METHODS: OXYS rats received SkQ1 eye drops (250 nM) from 9 to 12 months of age. Ophthalmoscopic examination was carried out before and after treatment. Light and electron microscopy were used for histomorphological examination. Expression of the Cryaa and Cryab genes was determined using real-time PCR. αB-crystallin expression was detected using Western blotting. RESULTS: SkQ1 completely prevented the cataract development in OXYS rats, and in some of the animals diminished the signs of the disease. Light and electron microscopy showed that SkQ1 attenuated the (typical for cataract) alterations in the lens capsule and epithelial cells, ameliorated disturbances of the hexagonal packing geometry of lens fibers, and improved ultrastructure of the epithelial cells. The levels of mRNA of α-crystallins genes which encode small heat shock proteins αA- and αB-crystallin that play a central role in maintaining lens transparency were significantly lower in the OXYS rats' lenses than in Wistar rats (control). SkQ1 normalized the level of mRNA of Cryaa, and significantly increased the level of Cryab mRNA as well as αB-crystallin protein in the lens of OXYS rats to the level of the control Wistar rats. CONCLUSION: SkQ1 eye drops hold promise as a treatment of cataract.

Age-related changes in the water-soluble lens protein composition of Wistar and accelerated-senescence OXYS rats.

PURPOSE: To determine the age-related and the cataract-specific changes in the crystallin composition in lenses of accelerated-senescence OXYS (cataract model) and Wistar (control) rats. METHODS: The water soluble (WS) and insoluble (WIS) fractions of the lens proteins were separated; the identity and relative abundance of each crystallin in WS fraction were determined with the use of two-dimensional electrophoresis (2-DE) and Matrix-Assisted Laser Desorption Ionization-Time Of Flight (MALDI-TOF) mass spectrometry. All statistical calculations were performed using the software package Statistica 6.0 by factor dispersion analysis (ANOVA/MANOVA) and Newman-Keuls post-hoc test for comparison of group mean values. RESULTS: The WIS protein content increased significantly in the aged animal lenses; the WIS/WS ratio increases in approximately 8 times to the age of 62 weeks. The interstrain difference was insignificant in this experiment. 2-DE maps of the young rat lenses (3 weeks) showed single spots for each lens protein while in older lenses (12 and 62 weeks) each crystallin was presented by several spots. The abundance of γA-γF-crystallins in WS fraction significantly decreases with age. A significant increase in the percentage abundance was also found for α-crystallins and ßB2-crystallin from 3 to 12 weeks. The major differences between Wistar and OXYS lenses are the faster decay of the content of γA-γF-crystallins in OXYS lenses, and the significant decrease of unmodified αA-crystallin abundance in old OXYS lenses. CONCLUSIONS: The presented results demonstrate that the increase of the water-insoluble (WIS) protein fraction is rather age-specific than cataract-specific phenomenon. The major age-related changes in WS protein composition are the fast insolubilization of γ-crystallins, and the increase of αB- and ßB2-crystallin abundance. The main interstrain differences, which could be attributed to the cataract-specific processes, are the faster decay of the content of γ-crystallins and the significant decrease of unmodified αA-crystallin abundance in the OXYS lenses.