Vol 88, No 11 (2023)

Номер посвящён памяти яркого учёного-геронтолога Алексея Матвеевича Оловникова, чьи теоретические работы об укорочении теломер лежали у истоков нового направления науки - молекулярной биологии старения. Алексей Матвеевич был членом редакционной коллегии журнала; с его лёгкой руки журнал стал регулярно публиковать статьи геронтологической тематики. Начало этой традиции положил номер, полностью посвященный проблемам старения и укорочению теломер, авторами которого были ведущие мировые специалисты в этой области, откликнувшиеся на приглашение Алексея Матвеевича (№ 11, 1997).

Relationships of growth, metabolism, reproduction, and body size to the biological process of aging and longevity have been studied for decades and various unifying “theories of aging” have been proposed to account for the observed associations. In general, fast development, early sexual maturation leading to early reproductive effort, as well as production of many offspring, have been linked to shorter lifespans. The relationship of adult body size to longevity includes a remarkable contrast between the positive correlation in comparisons between different species and the negative correlation seen in comparisons of individuals within the same species. We now propose that longevity and presumably also the rate of aging are related to the “pace-of-life.” A slow pace-of-life including slow growth, late sexual maturation, and a small number of offspring, predicts slow aging and long life. The fast pace of life (rapid growth, early sexual maturation, and major reproductive effort) is associated with faster aging and shorter life, presumably due to underlying trade-offs. The proposed relationships between the pace-of-life and longevity apply to both inter- and intra-species comparisons as well as to dietary, genetic, and pharmacological interventions that extend life and to evidence for early life programming of the trajectory of aging. Although available evidence suggests the causality of at least some of these associations, much further work will be needed to verify this interpretation and to identify mechanisms that are responsible.

The data on postmitotic instability of neuronal DNA, which have been reported in the last decade, are changing the theoretical landscape not only of neuroscience, but more broadly, of biology. A. M. Olovnikov suggested in 2003 that it is the DNA of neurons that can be the “initial substrate of aging”. The current data significantly increases the likelihood of this hypothesis. How does neuronal DNA accumulate damage, in what regions of the genome, what factors contribute to its accumulation, and how can they be associated with aging and the life span? These questions will be considered in the review. In addition, instability of the neuronal DNA had apparently been accompanied by a search for various ways to reduce the biological costs of brain function in Metazoan evolution. Phenomena such as sleep, an increase in the number of neurons in the vertebrate brain evolution, adult neurogenesis, distributed neuronal activity, somatic polyploidy, RNA editing in cephalopods can be reconsidered in the light of “DNA plasticity-instability trade-off” in neurons. The topic is of obvious importance not only for fundamental neuroscience, but also for translational medicine.

Transposable elements (TEs) comprise a significant part of eukaryotic genomes being a major source of genome instability and mutagenesis. Cellular defense systems suppress the TE expansion at all stages of their life cycle. Piwi proteins and Piwi-interacting RNAs (piRNAs) are key elements of the anti-transposon defense system, which control TE activity in metazoan gonads preventing inheritable transpositions and developmental defects. In this review, we discuss various regulatory mechanisms by which small RNAs combat TE activity. However, active transposons persist, suggesting these powerful anti-transposon defense mechanisms have a limited capacity. A growing body of evidence suggests that increased TE activity coincides with genome reprogramming and telomere lengthening in different species. In the Drosophila fruit fly, whose telomeres consist only of retrotransposons, a piRNA-mediated mechanism is required for telomere maintenance and their length control. Therefore, the efficacy of protective mechanisms must be finely balanced in order not only to suppress the activity of transposons, but also to maintain the proper length and stability of telomeres. Structural and functional relationship between the telomere homeostasis and LINE1 retrotransposon in human cells indicates a close link between selfish TEs and the vital structure of the genome, telomeres. This relationship, which permits the retention of active TEs in the genome, is reportedly a legacy of the retrotransposon origin of telomeres. The maintenance of telomeres and the execution of other crucial roles that TEs acquired during the process of their domestication in the genome serve as a type of payment for such a “service.”

Despite the use of preventive measures (including intense physical activity), cosmonauts and astronauts develop muscle atony and atrophy, insufficiency of the cardiovascular system, osteopenia, etc. All these changes, reminiscent of age-related physiological changes, occur in a healthy person in microgravity quite quickly - within a few months. Adaptation to the absence of gravity leads to the symptoms of aging, which are compensated after returning to Earth. The prospect of interplanetary flights raises the question of gravity thresholds, below which the main physiological systems will lose their functional potential, similar to aging, and affect life expectancy. An important role in the aging process belongs to the body’s cellular reserve - progenitor cells, which are involved in physiological remodeling and regenerative/reparative processes of all physiological systems. With age, progenitor cell count and the regenerative potential decreases. Moreover, their paracrine spectrum becomes pro-inflammatory during replicative senescence, disrupting tissue homeostasis. Mesenchymal stem/stromal cells (MSCs) are mechanosensitive, and therefore the absence of a gravitational stimulus causes serious changes in their functional status. The review compares the cellular effects of microgravity and changes developing in senescent cells, including stromal precursors.

In response to stress stimuli, eukaryotic cells typically suppress protein synthesis. This leads to the mRNA release from polysomes, their condensation with RNA-binding proteins, and the formation of non-membrane-bound cytoplasmic compartments called stress granules (SGs). SGs contain 40S but generally lack 60S ribosomal subunits. It is known that cycloheximide, emetine, and anisomycin, the ribosome inhibitors which block the 80S ribosome progression along mRNA and stabilize polysomes, prevent SG assembly. Conversely, puromycin, which induces premature termination, releases mRNAs from polysomes and stimulates the formation of SGs. The same effect is caused by some translation initiation inhibitors, which lead to polysome disassembly and the accumulation of mRNAs in a form of stalled 48S preinitiation complexes. Based on these and other data, it is believed that the trigger for SG formation is the presence of mRNA with extended ribosome-free segments, which tend to form condensates in the cell. In this study, we evaluated the ability of various small-molecule translation inhibitors to block or stimulate the assembly of SGs under conditions of severe oxidative stress induced by sodium arsenite. Contrary to expectations, we found that ribosome-targeting elongation inhibitors of a specific type, that arrest solitary 80S ribosomes at the beginning of the mRNA coding regions but do not interfere with all subsequent ribosomes in completing translation and leaving the transcripts (such as harringtonine, lactimidomycin, or T-2 toxin), completely prevented the formation of arsenite-induced SGs. These observations suggest that the presence of even a single 80S ribosome on mRNA is sufficient to prevent its recruitment into SGs, and the presence of extended ribosome-free regions of mRNA is not sufficient for SG formation. We propose that mRNA entry into SGs may be mediated by specific contacts between RNA-binding proteins and those regions on 40S subunits that remain inaccessible when ribosomes are associated.

The immune privileges of cancer stem cells are a well-known and widely studied problem, as the presence of such cells in tumors is associated with refractoriness, recurrence, and metastasis. Accumulating evidence also suggests the presence of immune privileges for non-pathologic stem cells in addition to their other defense mechanisms against damaging factors. This similarity between pathologic and normal stem cells raises the question of why stem cells have such a potentially damaging property. The regulation of vital processes of autoimmunity control and regeneration by interactions between immune cells, stem cells and their microenvironment are reviewed as determinants of stem cell immune privilege formation. A deep mutual integration in the regulation of stem and immune cells is noted. Based on the diversity and complexity of the mutual regulation of stem cells, their microenvironment and the immune system, I propose to use the term “stem system”.

The nucleotide excision repair (NER) system is responsible for removing a wide range of bulky damages from DNA, making a significant contribution to maintaining the stability of the genome. The efficiency with which the proteins of the NER system recognize and remove bulky damages depends on many factors and has important clinical and diagnostic significance. The review examines the current understanding of the molecular basis of the functioning of the NER system in eukaryotic cells, as well as analyzes the methods and approaches that are used to study the efficiency functioning of this DNA repair system both in vitro and ex vivo.

The creation of bioactive molecules for the treatment of cardiovascular diseases based on natural peptides stimulates intensive experimental research. In recent years, it has been established that the C-terminal fragments of apelin, an endogenous ligand of the APJ receptor, reduce metabolic and functional disorders in experimental heart damage. The review presents literature data and generalized results of our own experiments on the effect of apelin-13, [Pyr]apelin-13, apelin-12, and their chemically modified analogues on the heart in normal conditions and when modeling pathophysiological conditions in vitro and in vivo. It has been shown that the spectrum of action of apelin peptides on the damaged myocardium covers a decrease in the death of cardiomyocytes from necrosis, a decrease in cardiomyocyte membrane damage, an improvement in the metabolic state of the myocardium, and a decrease in the formation of reactive oxygen species and lipid peroxidation products. The mechanisms of the protective action of these peptides associated with the activation of the APJ receptor and the manifestation of antioxidant properties are discussed. The data presented in the review indicate the promise of molecular design of pharmacological APJ receptor agonists, which can serve as the basis for the development of cardioprotectors that affect the processes of free radical oxidation and metabolic adaptation.

In this paper the answer to O. B. Ptitsyn’s question “What is the role of conserved non-functional residues in apomyoglobin” is presented, which is based on the research results of three laboratories. The role of conserved non-functional apomyoglobin residues in formation of native topology in the molten globule state of this protein is revealed. This fact allows suggesting that the conserved non-functional residues in this protein are indispensable for fixation and maintaining main elements of the correct topology of its secondary structure in the intermediate state. The correct topology is a native element in the intermediate state of the protein.

Progesterone exerts multiple effects in different tissues through nuclear receptors (nPRs) and through membrane receptors of the adiponectin and progestin receptor (mPRs) family. The effect of progesterone on cells through different types of receptors can vary significantly. At the same time, it affects the processes of proliferation and apoptosis in normal and tumor tissues in a dual way, stimulating proliferation and carcinogenesis in some tissues, suppressing them and stimulating cell death in others. In this study, we have shown the presence of a high level of mRNA and mPRβ protein in HepG2 tumor cells of human hepatocellular carcinoma. Expression of other membrane and classical nuclear receptors was not detected. May be mPRβ has an important function in HepG2 cells. The main goal of the work was to study the function of this protein and the mechanisms of its action in human hepatocellular carcinoma cells. Previously, we have identified selective mPRs ligands, compounds LS-01 and LS-02, which do not interact with nuclear receptors. Their employment allows differentiating the effects of progestins mediated by different types of receptors. The work studied the effects of progesterone, LS-01 and LS-02 on the proliferation and death of HepG2 cells, as well as the activating phosphorylation of two kinases, p38 MAPK and JNK, under the action of three steroids. It was shown that all three progestins after 72 hours of incubation with cells suppressed their viability and stimulated the appearance of phosphatidylserine on the outer surface of membranes, which was detected by binding to V-FITC annexin, but they did not affect DNA fragmentation of cell nuclei. Progesterone significantly reduced the expression of proliferation marker genes and stimulated the expression of the p21 protein gene, but had a suppressive effect on the expression of some proapoptotic factor genes. All three steroids activated JNK in these cells, but had no effect on p38 MAPK activity. The effects of progesterone and selective mPRs ligands in HepG2 cells were the same in terms of suppression of proliferation and stimulation of apoptotic changes in outer membranes, therefore, they were mediated through interaction with mPRβ. JNK is a member of the signaling cascade activated in these cells by the studied steroids.