The article gives a brief description of geroprotection and rejuvenation methods known to date, presenting their main mechanisms and limitations. To overcome the main limitations of the process of rejuvenation, it is possible to use a process called “cell autocloning.” The principle of the proposed method of rejuvenation is as follows: a periodic process of autocloning of the cell nucleus is initiated in the cellular genome with the formation of one unstable daughter copy and its subsequent self-elimination. In this case, the process of cell division stops in the phase of nuclei divergence without subsequent physical separation of the cell itself. This is especially important for postmitotic cells, where the looping of the “unidirectional” line of the ontogenesis program into a “ring” will mean their transition into renewable cells. The prototype for autocloning mechanisms could be the already known ways in which cells adapt to the increasing amount of their damage over time. These are polyploidy and asymmetric cell division, relying on which it is possible to obtain a renewable process of cell nuclei division, when only the original nucleus remains as a result of division. Although this is not a simple task, there are possible pathways to its solution using approaches that can suggest modern knowledge from the field of molecular and cell biology and genetics. The realization of such a goal will require a lot of work, but the expected result justifies it.
Introduction
The very concept of rejuvenation means an impact aimed essentially at trying to transform an old organism into a young one (Zhang et al., 2022). The success of such effects is directly related to our level of understanding of aging mechanisms. Here it is necessary to emphasize the difference between rejuvenation and geroprotection. If in the first case the goal is radical rejuvenation of the whole organism, the essence of geroprotection is to slow down involutional processes as much as possible, to reduce the rate of progression of this or that pathology, to delay the time of occurrence of unfavorable changes. Geroprotection is aimed not at the root cause of aging, but at individual signs and mechanisms associated with aging. In addition, the effect of geroprotective effects is transient (Salnikov and Baramiya, 2021). Success in the pathway of rejuvenation requires an understanding of the causes and basic mechanisms of aging. The problem of understanding the processes of aging remains important, despite the huge number of works devoted to this topic (de Magalhães, 2024). From our point of view, it is necessary to distinguish between the causes and mechanisms of realization of this process. Aging itself manifests itself at the level of multicellular organisms, hence its main mechanisms are realized exactly where a cell receives in addition to its needs the necessity to perform organismal functions (Salnikov and Baramiya, 2020). When considering the causes of aging, we assume that the main cause of aging is embedded in the very “design” or principle of multicellular organization. Let us briefly explain this statement. Evolutionarily, multicellular organisms developed on the basis of unicellular colonies, gradually acquiring new genes that provide integrative functions peculiar to the organism. At the same time, the cells that make up the organism retain their original genes that provide all their basic needs. Thus, in the cells of an organism it is always possible to distinguish an evolutionarily conservative part of the genome responsible for providing cellular infrastructure, i.e., housekeeping genes (HG), and an evolutionarily active part of the genome providing all organismal functions, i.e., integrative genes (IntG). The described ratios of the functional parts of the cellular genome, were shown by us when analyzing the age-dependent production of their RNA (Salnikov et al., 2023; Salnikov et al., 2024). We emphasize that only the IntG part of the genome is regulated by the developmental program, or ontogenesis (Salnikov, 2022). Thus, the cells of the organism are constantly facing a choice: either slowing down the rate of division, leading to a decrease in the cost of their own repair, or transition to uncontrolled division, which is essentially carcinogenesis.
Proponents of the entropic theory of aging emphasize (Perevoshchikova and Fedichev, 2024) that entropy increases with age both in the organism as a whole and in its individual cells, without commenting on the practical “immortality” of single-cell or tumor cells. It turns out that the very aggregation of cells into an organism causes aging processes. Also, like aging, carcinogenesis is the price to pay for multicellularity. Oncogenesis is of great interest for understanding of aging processes due to one important fact - cells that give rise to cancer are immortal. The HeLa line has been maintained for seven decades without showing signs of degradation. In fact, we observe it as a single-cell culture (Salnikov and Baramiya, 2021). The genome of differentiated cells of an organism is “designed” by evolution in such a way that in prophase, or after mitosis is completed, the activity of the genome is switched to fulfill organismal functions, creating over time a deficit of resources needed by the cell for repair. Maintaining the repair balance depends on the rate of division for each tissue, or the ratio of stimulatory and inhibitory signals in the cell - switching from HG to IntG at the tissue and cellular levels. Each tissue type has its own program for achieving the necessary maturity. Their total work creates the aging trajectory (Gems et al., 2023), in which highly differentiated cells play an important role. These are the cells from which senescent cells are formed in the course of aging, which are also a target for geroprotective interventions. It is important to note that the very definition of senescent cells (Moiseeva et al., 2023) always refers to postmitotic, or rarely dividing cells with low mitotic index (MI). The organism tissues consisting of such highly differentiated cells play not only a major role in the functioning of the organism, but also in aging processes. The increasing number of senescent cells with a deficit of reparative capabilities that occurs with age naturally leads to the accumulation of cytotoxic products and associated metabolic disorders in them and in their environment (Nelson and Masel, 2017). As a result, tissues with high MI are subjected to increasing metabolic pressure from an increasing mass of slowly dividing and postmitotic cells. For actively dividing cells of constantly renewing tissues like bone marrow, intestinal and mucous membrane epithelium, and the growth layer of the skin, such toxic exposure leads to a gradual decrease in their stem cell numbers and a reduced rate of regeneration. Agreeing with the definition of the phenomenon “aging” itself. As a phenomenon of incomplete recovery or repair of cellular disorders arising during life (Lagunas-Rangel and Bermúdez-Cruz, 2019; Ferreira et al., 2021; Salnikov 2022), we obtain a reliable criterion for assessing any effects aimed at rejuvenation.