The cure for aging: geroprotectors of the new generation
Report of Academician V.P. Skulachev
"New generation geroprotectors: penetrating cations as nanotransporters of antioxidants in mitochondria"
at the forum "Rosnanotech-2009", the section "Nanotechnology in medicine: immunobiological drugs and targeted drug delivery".
Published on the Abercade website.
Recently, we have developed a concept suggesting that aging is a genetically programmed process, which is the last stage of individual development of the organism (ontogenesis). We believe that the aging program appeared in the process of biological evolution as a way to accelerate this evolution. Within the framework of such a concept, human aging should be considered as an atavism, since people no longer depend on evolution, since it is carried out too slowly.
If aging is programmed, then breaking this program can prevent aging in the same way that inhibiting the cell death program (apoptosis) prevents cell death. There are many indications that the aging program leads to the extinction of physiological functions of the body due to the action of toxic derivatives of O2 (reactive oxygen species, ROS), which are formed in mitochondria, intracellular organelles that serve as the main consumers of O2 in the cell. Therefore, antioxidants addressed to the mitochondria can be inhibitors of the aging program. To investigate this possibility, a project was formed with the participation of several groups of researchers from Russia, Sweden and the USA. A new type of compounds (SkQ) was synthesized, consisting of plastoquinone (the antioxidant part), a penetrating cation and a decane or pentane linker (Fig.1).
Fig. 1. Formulas SkQ1 (left) and C12TRP (right)
The working hypothesis was that such positively charged compounds would specifically accumulate in the 2 nm layer of the inner mitochondrial membrane, since these organelles are the only negatively charged compartment of a living cell. In this case, the cationic part of the SkQ molecule can serve as a nanometer-sized "electric locomotive" transporting the antioxidant. In experiments using a flat bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest penetration, namely 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1), 10-(6'-plastoquinonyl) decylrodamine 19 (SkQR1), and 10-(6'-methylplastoquinonyl)-decyltriphenylphosphonium (SkQ3). Anti- and pro-oxidant properties of the selected compounds, as well as 10-(6'-ubiquinonyl)decyltriphenylphosphonium (MitoQ) was tested in aqueous solutions, on micelles, liposomes, BLM, isolated mitochondria and cell cultures and organisms. Experiments with mitochondria have shown that micromolar concentrations of the studied compounds have a pro-oxidant effect, but lower (nanomolar) concentrations exhibit antioxidant activity, which falls in the series SkQ1=SkQR1 > SkQ3 > MitoQ. It has been shown that SkQ1 is able to be restored by the mitochondrial respiratory chain, i.e. this compound is a renewable antioxidant. Under conditions of oxidative stress, SkQ1 specifically prevented the oxidation of mitochondrial cardiolipin. In cell cultures, SkQR1 (a fluorescent derivative of SkQ) stained exclusively mitochondria. Extremely low concentrations of SkQ1 and SkQR1 blocked apoptosis of HeLa cells and human fibroblasts caused by the action of H2O2. Higher concentrations of SkQ were required to protect cells from necrosis caused by ROS. Experiments with fungi Podospora anserina, crustaceans Ceriodaphnia affinis, fruit flies, fish Nothobranchius fuzreri and mice have shown that SkQ1 lengthens the median lifespan of organisms.
In mammals, the effect of SkQ on aging is accompanied by a sharp slowdown in the development of age-dependent pathologies such as cataract, retinopathy, glaucoma, baldness, depression, graying, osteoporosis, disappearance of the estrous cycle in females and libido in males, hypothermia, lipid and protein peroxidation, etc. SkQ1 practically excluded infectious diseases from the list of causes of mortality. In all likelihood, this was due to the prevention of an age-dependent decrease in immunity. It turned out that SkQ1 slows down the age-related involution of the thymus and the spleen follicle, where T- and B–lymphocytes, respectively, are formed - key components of the body's immune defense. In addition, we have shown that SkQ1 has a strong therapeutic effect on already developed retinopathy, especially on congenital retinal dysplasia and cataracts. With the help of drops containing 250 nM SkQ1, the vision of 67 of 89 animals (dogs, cats, horses) blinded due to retinopathy was restored. SkQ1 drops prevented the loss of vision of rabbits in the experimental uveitis model and restored vision to animals already blinded by uveitis. The beneficial effect of the same drops was also manifested in the model of experimental glaucoma. In addition, pre-administration of SkQ1 to rats dramatically reduced the arrhythmia of isolated hearts caused by ischemia or H2O2. SkQ1 significantly reduced the area of damage in myocardial infarction or stroke, and also prevented the death of animals with renal ischemia. In p53–/–mice, SkQ1 at a dose of 5 nmol/kg per day reduced the level of ROS in the spleen and inhibited the appearance of lymphomas to the same extent as the traditional antioxidant N-acetylcysteine added at a million times higher concentration. Recently, our group has shown that SkQ1 and C12TPP (an analogue of SkQ, but without plastoquinone, see Figure 1) can work as nanotransporters of fatty acid anions through model and natural membranes (Figure 2).
Fig. 2. Transmembrane transfer of fatty acid anions by C12TRP cation
In this case, they catalyze the circulation of fatty acids in the mitochondria, which leads to a mild disconnection of the processes of respiration and energy storage, a decrease in membrane potential and, as a consequence, a decrease in the production of ROS by mitochondria. This can mimic calorie restriction, which is known to prolong the life of a variety of organisms (from yeast to mammals). Thus, it can be argued that the compounds of the SkQ group are a promising tool for the treatment of aging, as well as age-dependent pathologies.
Portal "Eternal youth" http://vechnayamolodost.ru22.10.2009