Volume 89, Nº 2 (2024)

Quinone derivatives of triphenylphosphonium have proven themselves to be effective geroprotectors and antioxidants that prevent the oxidation of cell components with the participation of active free radicals – peroxide (RO2•), alkoxy (RO•), alkyl (R•), as well as reactive oxygen species (superoxide anion, singlet oxygen). The most studied representatives are derivatives of plastoquinone (SkQ1) and ubiquinone (MitoQ), which in addition to antioxidant properties also had a strong antibacterial effect. Other quinone derivatives based on decyltriphenylphosphonium (SkQ3, SkQT, and SkQThy) have been less studied and their antibacterial activity remains undiscovered. In this work, we investigated the antibacterial properties of quinone derivatives based on decyltriphenylphosphonium. We have shown that, as in the case of SkQ1, they are effective against various gram-positive bacteria, while they are not so effective against gram-negative bacteria. This is associated with their recognition by the main multidrug resistance pump of gram-negative bacteria AcrAB-TolC. Moreover, in the case of SkQ1 itself, there is a dependence of its action on the number of bacterial cells and the molar amount of the antibiotic itself, which distinguishes it from conventional antibiotics. At the same time, the cytotoxic effect on mammalian cells is observed in higher concentrations, which suggests the presence of a protective effect caused by the separation of the process of energy generation and transport on the cell membrane. Another possible explanation could be the different composition of multidrug-resistant (MDR) pumps. The difference in cytotoxic effects on mammalian cells may be due to different expression profiles of MDR pumps in different cell types.

Genes of putative reductases of α,β-unsaturated carboxylic acids are abundant among anaerobic and facultatively anaerobic microorganisms, yet substrate specificity has been experimentally verified for few encoded proteins. Here, we co-produced in Escherichia coli a heterodimeric protein of the facultatively anaerobic marine bacterium Vibrio ruber (GenBank SJN56019 and SJN56021; annotated as NADPH azoreductase and urocanate reductase, respectively) with Vibrio cholerae flavin transferase. The isolated protein (named Crd) consists of the sjn56021-encoded subunit CrdB (NADH:flavin, FAD binding 2, and FMN bind domains) and an additional subunit CrdA (SJN56019, a single NADH:flavin domain) that interact via their NADH:flavin domains (Alphafold2 prediction). Each domain contains a flavin group (three FMNs and one FAD in total), one of the FMN groups being linked covalently by the flavin transferase. Crd readily reduces cinnamate, p-coumarate, caffeate, and ferulate under anaerobic conditions with NADH or methyl viologen as the electron donor, is moderately active against acrylate and practically inactive against urocanate and fumarate. Cinnamates induced Crd synthesis in V. ruber cells grown aerobically or anaerobically. The Crd-catalyzed reduction started by NADH demonstrated a time lag of several minutes, suggesting a redox regulation of the enzyme activity. The oxidized enzyme is inactive, which apparently prevents production of reactive oxygen species under aerobic conditions. Our findings identify Crd as a regulated NADH-dependent cinnamate reductase, apparently protecting V. ruber from (hydroxy)cinnamate poisoning.

Over the past decades, an unimaginably large number of attempts have been made to restore the structure of mammalian organs after damage by introducing stem cells into them. However, this procedure does not lead to a full recovery. At the same time, it is known that complete regeneration (restitution without fibrosis) is possible in organs with proliferating parenchymal cells. An analysis of such models allows us to conclude that the most important condition for the repair of the histological structures of an organ (in the presence of a stem cells) is the preservation of collagen frame structures in it, which serve as “guide rails” for proliferating and differentiating cells. An alternative condition for the complete reconstruction of organ structures is the presence of a free “morphogenetic space” consisting of a gel-like matrix of the embryonic-type connective tissue, which takes place in embryonal development of organs in mammalians or during complete regeneration in amphibians. Approaches aimed at preserving scaffold structures or creating a “morphogenetic space” could radically improve the results of organ regeneration using both local and exogenous stem cells.

AgeMeta is a database that provides systemic and quantitative description of mammalian aging at the level of gene expression. It encompasses transcriptomic changes with age across various tissues of humans, mice, and rats, based on a comprehensive meta-analysis of 122 publicly available gene expression datasets from 26 studies. AgeMeta provides an intuitive visual interface for quantification of aging-associated transcriptomics at the level of individual genes and functional groups of genes, allowing easy comparison among various species and tissues. Additionally, all the data in the database can be downloaded and analyzed independently. Overall, this work contributes to the understanding of the complex network of biological processes underlying mammalian aging and supports future advancements in this field. AgeMeta is freely available at: https://age-meta.com/.

The most important manifestation of aging is an increased risk of death with advancing age, a mortality pattern characterized by empirical regularities known as mortality laws. We highlight three significant ones: the Gompertz law, compensation effect of mortality (CEM), and late-life mortality deceleration and describe new developments in this area. It is predicted that CEM should result in declining relative variability of mortality at older ages. The quiescent phase hypothesis of negligible actuarial aging at younger adult ages is tested and refuted by analyzing mortality of the most recent birth cohorts. To comprehend the aging mechanisms, it is crucial to explain the observed empirical mortality patterns. As an illustrative example of data-directed modeling and the insights it provides, we briefly describe two different reliability models applied to human mortality patterns. The explanation of aging using a reliability theory approach aligns with evolutionary theories of aging, including idea of chronic phenoptosis. This alignment stems from their focus on elucidating the process of organismal deterioration itself, rather than addressing the reasons why organisms are not designed for perpetual existence. This article is a part of a special issue of the journal that commemorates the legacy of the eminent Russian scientist Vladimir Petrovich Skulachev (1935-2023) and his bold ideas about evolution of biological aging and phenoptosis.

The article describes the history of studies of survival data carried out at the Research Institute of Physico-Chemical Biology under the leadership of Academician V. P. Skulachev from 1970s until present, with special emphasis on the last decade. The use of accelerated failure time (AFT) model and analysis of coefficient of variation of lifespan (CVLS) in addition to the Gompertz methods of analysis, allows to assess survival curves for the presence of temporal scaling (i.e., manifestation of accelerated aging), without changing the shape of survival curve with the same coefficient of variation. A modification of the AFT model that uses temporal scaling as the null hypothesis made it possible to distinguish between the quantitative and qualitative differences in the dynamics of aging. It was also shown that it is possible to compare the data on the survival of species characterized by the survival curves of the original shape (i.e., “flat” curves without a pronounced increase in the probability of death with age typical of slowly aging species), when considering the distribution of lifespan as a statistical random variable and comparing parameters of such distribution. Thus, it was demonstrated that the higher impact of mortality caused by external factors (background mortality) in addition to the age-dependent mortality, the higher the disorder of mortality values and the greater its difference from the calculated value characteristic of developed countries (15-20%). For comparison, CVLS for the Paraguayan Ache Indians is 100% (57% if we exclude prepuberty individuals as suggested by Jones et al.). According to Skulachev, the next step is considering mortality fluctuations as a measure for the disorder of survival data. Visual evaluation of survival curves can already provide important data for subsequent analysis. Thus, Sokolov and Severin [1] found that mutations have different effects on the shape of survival curves. Type I survival curves generally retains their standard convex rectangular shape, while type II curves demonstrate a sharp increase in the mortality which makes them similar to a concave exponential curve with a stably high mortality rate. It is noteworthy that despite these differences, mutations in groups I and II are of a similar nature. They are associated (i) with “DNA metabolism” (DNA repair, transcription, and replication); (ii) protection against oxidative stress, associated with the activity of the transcription factor Nrf2, and (iii) regulation of proliferation, and (or these categories may overlap). However, these different mutations appear to produce the same result at the organismal level, namely, accelerated aging according to the Gompertz’s law. This might be explained by the fact that all these mutations, each in its own unique way, either reduce the lifespan of cells or accelerate their transition to the senescent state, which supports the concept of Skulachev on the existence of multiple pathways of aging (chronic phenoptosis).