key: cord-1046240-uqmq1tu4 authors: Shilovsky, Gregory A.; Putyatina, Tatyana S.; Markov, Alexander V. title: Altruism and Phenoptosis as Programs Supported by Evolution date: 2021-12-17 journal: Biochemistry (Mosc) DOI: 10.1134/s0006297921120038 sha: 38df030de3cfcd78986352bf7ce25014720b033c doc_id: 1046240 cord_uid: uqmq1tu4 Phenoptosis is a programmed death that has emerged in the process of evolution, sometimes taking the form of an altruistic program. In particular, it is believed to be a weapon against the spread of pandemics in the past and an obstacle in fighting pandemics in the present (COVID). However, on the evolutionary scale, deterministic death is not associated with random relationships (for example, bacteria with a particular mutation), but is a product of higher nervous activity or a consequence of established hierarchy that reaches its maximal expression in eusocial communities of Hymenoptera and highly social communities of mammals. Unlike a simple association of individuals, eusociality is characterized by the appearance of non-reproductive individuals as the highest form of altruism. In contrast to primitive programs for unicellular organisms, higher multicellular organisms are characterized by the development of behavior-based phenoptotic programs, especially in the case of reproduction-associated limitation of lifespan. Therefore, we can say that the development of altruism in the course of evolution of sociality leads in its extreme manifestation to phenoptosis. Development of mathematical models for the emergence of altruism and programmed death contributes to our understanding of mechanisms underlying these paradoxical counterproductive (harmful) programs. In theory, this model can be applied not only to insects, but also to other social animals and even to the human society. Adaptive death is an extreme form of altruism. We consider altruism and programmed death as programmed processes in the mechanistic and adaptive sense, respectively. Mechanistically, this is a program existing as a predetermined chain of certain responses, regardless of its adaptive value. As to its adaptive value (regardless of the degree of “phenoptoticity”), this is a characteristic of organisms that demonstrate high levels of kinship, social organization, and physical association typical for higher-order individuals, e.g., unicellular organisms forming colonies with some characteristics of multicellular animals or colonies of multicellular animals displaying features of supraorganisms. The problem whether biological evolution could nat urally lead to the development of counterproductive (harmful to an individual) programs has been debated for more than 50 years. The opponents of this idea claim (see the history of this issue in [1, 2] ) that the development of such programs as aging and lifespan limitation under the pressure of selection is impossible, because individuals in which these programs are disrupted (e.g., due to random mutations) receive reproductive advantage and will dis place the carriers of the counterproductive programs. However, the study demonstrating that mutation in the insulin receptor gene daf 2/IGF 1 could more than dou ble the lifespan (LS) of the nematode Caenorhabditis ele gans [3] has rekindled the discussion on possible adaptive advantages of aging. It has been suggested that the wild type daf 2 allele could provide selective advantage through the increased genetic diversity or decreased com petition between parents and offspring in the species with short LS [3] . The adaptivity of aging and death programs predicted long ago by Weismann [4] has been recently confirmed, first, through mathematical modeling [5] , and next, in the studies by the D. Gems group [6 8 ]. This has shifted the discussion on the emergence of counterpro ductive programs in the course of evolution from the philosophical to the scientific one. Under certain circumstances, programs that had ini tially developed as protective ones could become counter productive. These include inflammation, which is not a disease per se, but rather a response of an organism to pathology at a certain location. However, if no cure is provided and the disease becomes chronic, inflammation could bring even more suffering than the disease itself, and could facilitate inflammaging [9] . Wang and Medzhitov [10] postulated the existence of correlation between thermoregulation, metabolism, and host response to infection. According to the authors, immune system utilizes body temperature regulation as a strategy to control the rate of metabolism, which, in turn, pro motes the resistance to the inflammation associated damage. Let's look at the pain syndromes as an example. Pain is definitely useful as it informs an organism on injury or unacceptable parameters of external or internal medium (temperature, etc.). However, chronic pain could make an individual to suffer, so that the only thought would be on how to switch off this system, which is actually most useful from the evolutionary point of view. At present, pharmaceutical companies spend a lot of money on the development of anti inflammatory and anti allergic preparations, as well as on painkillers. The mechanism of pathology development has been explained by Ye and Medzhitov [11] , who imagined the homeostatic state as a ball inside a parabolic shape hole of the norm. When some factors attempt to throw the sys tem off balance, homeostasis regulating factors will try to bring the system back, similarly to the ball rolling back to the bottom of the hole under the force of gravity. However, excessive acceleration of the ball (even for the fast stabilization at the hole bottom) could bring it outside of the hole without the possibility to come back, and in this case, the system cannot return to the normal state. The inflammatory response is required to restore the equilibrium, but in the case of severe pathology, this response could push the system further away from the norm, which could result in its stabilization in the state of chronic pathology. In particular, inflammation could develop in response to allergens and poisons, tissue damage, stress conditions (environmental factors, unhealthy life style), and, obviously, infection. In all these cases, such response is evolutionary and physiologically justified, as it protects the organism by removing harmful agents, conditions, and "invaders", and restores the damage. However, excessive response could cause problems, e.g., develop ment of allergy due to the excessive hostility towards for eign (even harmless) compounds. Continuous fight against infection could lead to the emergence of autoim mune response and even sepsis. Pathological tissue heal ing could cause fibrosis and cancer. Severe allergic reac tion can lead to rapid health deterioration, shock, or death, even if the original allergen itself is relatively harm less. The failure of the body defense systems could be the reason for autoimmune diseases, which are, however, caused by the highly programmed immune response. It is commonly recognized now that the immune response is stimulated by different damage associated molecular pat tern molecules, DAMPs, and pathogen associated molecular patterns, PAMPs. These molecules are quite diverse structurally and could be both of protein (endoge nous heat shock proteins S100 or HMGB1) and non pro tein nature (uric acid, heparin sulfate, mono and poly saccharides). The same effect is observed when DNA is present anywhere other than the nucleus and mitochon dria, as well as when nucleotides (ATP) and nucleosides (adenosine) are found at high concentrations outside the cell [12, 13] . However, the most known counterproductive pro grams that could emerge (and emerged) in the course of biological evolution are phenoptosis and altruism. The term "phenoptosis" was first introduced in the literature by Professor V. P. Skulachev in 1997 [14] (see also [15 18] ). According to the definition, phenoptosis is the most counterproductive program among all men tioned above, as it leads to death. The issue of the programmed nature of slow (chron ic) phenoptosis (aging) is complicated by the ambiguity of the term "programmed aging" [19, 20] , which could lead in logical confusion [6] and should be eliminated to avoid conceptual errors. The word "aging" in the term "programmed aging" should not be referred to all changes occurring with age (including favorable changes associated with matura tion), but rather to the age related changes associated with the organism deterioration (or biological aging) [7] , implying that such program has developed under the selection pressure to increase adaptability. Cell cycle program can decrease the organism adaptability, as in the case of cell proliferation in malig nant tumors [7] . Blagosklonny [21] suggested the term "quasi program". In this case, aging (similar to continu ing growth during the development) would be due to an inadequately intense cell functioning. The theory of hyperfunctioning quasi programmed aging explains inflammation and immune aging, hyperinflammation, hyperthrombosis, hypothrombosis, and cytokine storm associated with the age related increase in the organism BIOCHEMISTRY (Moscow) Vol. 86 Nos. 12 13 2021 susceptibility to COVID 19. Hence, programmed aging was divided into adaptive and non adaptive (or pro grammed and quasi programmed). On the other hand, to protect from this type of death, mammals in the process of their evolution have lost necroptosis several times: either via the absence of central components of necroptosis, such as RIPK3 (receptor interacting pro tein kinase 3) and MLKL (mixed lineage kinase domain like protein) important in etiology and development of many disease with the increased risk of death (ischemic damage and sepsis) or due to inactivating mutations in these proteins (frameshifts mutations or premature stop codons) [22] . Increased diversity and complexity of counterpro ductive programs is a consequence of the emergence of organized communities (societies, herds, flocks, etc.) consisting of multiple individual organisms. These com munities are capable of performing coordinated actions similarly to how individual cells in a multicell organism behave. However, cell functioning in a multicellular organism is coordinated by special centralized regulatory systems (e.g., nervous system), which are lacking in the groups of individual organisms. Hence, the actions of such individual organisms are coordinated by other mechanisms, including quorum sensing. The key signal triggering the mechanism of community formation is often crowding. When the concentration of signaling molecules exceeds a certain threshold, global gene expression patterns change due to quorum sensing [23] . For example, Vibrio fischeri bacteria start to emit light only when a certain cell density is reached [24] . The dif ferences in the composition of human gut microbiota are associated with pathologies, e.g., inflammatory diseases. Bacteria communicate with each other with the help of extracellular molecules (autoinducers) in the process termed quorum probing [25, 26] . It is assumed that bac teria communicate with each other and with their host, and the information on these interactions affects the pop ulation density and species composition of commensal bacteria, as well as the physiology of the host cells [25, 26] . Altruism is commonly considered to involve behav ioral strategies and actions that are unfavorable for an individual, but provide advantage to other members of the community (with respect to reproduction and adapta tion). In a biological sense, altruism is a type of behavior resulting in the increase of adaptability (and, as a result, reproductive success) of other community members at the expense of the chance of successful reproduction of the altruistic individual. In this article, we discuss the mechanisms behind the evolutionary emergence and modifications of such coun terproductive program as altruism, one of the high level manifestations of which is phenoptosis (i.e., when an individual helps others at the expense of its own repro duction and life). Altruism could be divided into two distinct types. In the first case, an individual becomes an altruist passively under the effects of the environment, without any inter nal changes. These environmental factors could be changes in other individuals (e.g., cheaters), or when an individual is forced to become an altruist in the commu nities with strong hierarchy. In the second case, an indi vidual becomes an altruist actively due to the changes it its own organism. At the first glance, emergence of the latter type of altruism in the evolution, the driving force of which is absolutely egoistic natural selection, seems par adoxical. However, natural selection implies automatic and unbiased evaluation of all favorable and unfavorable effects on all allele copies in the population -if advan tages overweight disadvantages, this allele propagates. Hence, from the "altruistic allele" point of view, this sit uation is not altruistic at all, but pure egoism. This allele forces all its carriers to perform altruistic acts and to sac rifice several of its copies in order to bring advantage to its other copies. The moving force of evolution is natural selection of random hereditary changes [27] . If organisms pass down their individual features to the offspring, if these features change randomly sometimes, and finally, if at least some of these changes increase the probability of reproduction, then the future generations of these species must become more perfect without any external interven tion. In this case, perfection is understood as adaptability manifested as the reproduction efficiency [28] . Altruistic sacrifice of one's reproduction could be either partial or complete. In the latter case, it is in essence phenoptosis (phenoptotic altruism) with the differ ence that it is the offspring and not the individual that gets eliminated. The mechanisms of altruism emergence. There are multiple ways for the altruism to emerge in the evolution. In particular, it can appear as a result of kin selection. The Hamilton rule asserts that an altruistic gene (more pre cisely, allele facilitating altruistic behavior) will be favored by selection and will propagate in the population, thus eliminating the competing "selfish allele" from the gene pool. If nrB > C, where r is the genetic relatedness of the altruist to the beneficiary; B is the reproductive benefit gained by the recipient of the altruistic act; C is the repro ductive cost to the individual performing the act, and n, number of recipients of the altruistic act. If nrB > C, the altruistic allele will automatically and inevitably increase its frequency in the population gene pool. Other mechanisms of the evolution of altruism are not directly associated with the relatedness between the altruists and beneficiaries. For example, the Simpson's paradox describes a situation when a total fraction of altruists increases in the entire population even if in each local group, altruists lose to egoists in competition and BIOCHEMISTRY (Moscow) Vol. 86 Nos. 12 13 2021 their fraction decreases. This phenomenon was experi mentally demonstrated for two modified laboratory strains of Escherichia coli [29] . The essence lies in the fact that if the number of founders of a new group is low, which happens when the population is dispersed, this group can randomly contain an increased percent of altruists. Due to initial abundance of altruists, the number of individuals in this group will increase fast, while groups including a higher proportion of egoists will grow slower. As a result, the Simpson's paradox will ensure the total growth of the fraction of altruists in the entire population. Population bottlenecks (i.e., periods of significant decline in the population size followed by its restoration) can serve as analogy of fractionation (partition of cells between test tubes) in nature. This occurs, for example, when new substrates are seeded with very low numbers of microbial "progenitors". Egoistic evolution of individual symbionts within a cooperating system is impossible in the case of their genet ic homogeneity, i.e., in the absence of variability, which is one of the main components of Darwin's evolution. The mechanism for the maintenance of genetic homogeneity in symbionts of termites of the Macrotermitinae subfamily is very interesting. The ter mites collect spores of Termitomyces fungi in the vicinity of the nest to create fugal gardens. The initial seeding material is genetically diverse; however, each host colony is associated with a single fungal symbiont [30] . It was found that genetically identical Termitomyces mycelia help each other (but not other mycelia) to generate coni dia [30] , which eventually results in the formation of monoculture. When the evolution could not ensure the identity of cooperators, the hosts have to fight against egoists using different methods or to rely on the mechanisms ensuring the balance between the number of egoists and noble cooperators (Simpson's paradox, or balancing selection). The discussed examples suggest that if it were not for the problem of cheaters emerging due to the lack of evo lutionary preference for the benefit of species (and not the gene) and the absence of evolutionary foresight, cooperation and altruism could have become the domi nating forms of relationships between the organisms on our planet. But evolution is blind and, hence, coopera tion develops only when a certain set of circumstances either curb the number of cheaters or prevent their emer gence. It could be stated in conclusion that natural selection could ensure altruism development under certain circum stances, even if it favors egoists in each separate group (community), condemning altruists to gradual extinction. The spectrum of conditions that facilitate the Simpson's paradox is quite narrow; that is why its role in nature is likely insignificant. Genetic basis of altruism in humans. When speaking about altruism evolution in primates, especially in humans (regular biological evolution based on gene selec tion), one must also consider social and cultural evolu tion that implies selection of ideas and memes (such as moral and ethical standards, rules of conduct in the soci ety, etc.), as well as the intergroup competition [31, 32] . Twin studies revealed that the inclination to kind ness, trustfulness, and thankfulness is of genetic nature. These features are partly hereditary and at least by 10 20% are determined by the genes [33] . This means that biological evolution of altruism in humans has not fin ished. Human population is still characterized by genetic polymorphism that determines higher or lower inclina tion for cooperative behavior and mutual trust. Depending on the environmental, social, and economic conditions, natural selection might favor either trustful cooperators or wary egoists, and the variability of these conditions maintains the existing diversity. This could also be explained by the frequency dependent balancing selection: the more trustful altruists are around you, the more profitable it becomes to nonreciprocally benefit from other's kindness. However, if the number of such parasites is high, their strategy becomes less profitable; the society starts to perceive them as a real threat and implements measures to curb egoism. Several genes have been identified that affect human personality, including moral qualities [34] . For example, intranasal administra tion of oxytocin in humans increases their inclination to express selfless altruism [35] . Similar effects have been found for the allele variants of the AVPR1a vasopressin receptor gene and oxytocin receptor gene (OXTR) [36] . Altruism and society. Some authors state that real selfless altruism toward non kin is very rare in nature [37] . At the same time, parochial altruism (benefit to the in group) is common for humans, and such in group does not have to include blood relatives only. Indeed, observing human society reveals that many peo ple selflessly help and support non relatives over relatives. In this case, the preference is to the "kindred spirits". Very often this involves supporting people with attractive (and new before their first expression) ideas. In developed countries, help is provided mainly in a form of money; in poor countries, other forms of support are more com mon. At the same time, people do not support those they do not like (even if they are blood relatives). The closest relatives are often an exception, since it is customary to help them in any situation (this refers primarily to the Western industrial societies, while in the traditional soci eties, social institutes based on kinship are more devel oped [37] ). In reciprocal altruism, individuals behave altruisti cally to each other, but only in the case when they expect reciprocal sacrifice [38] . This can be observed in animals that are sufficiently intelligent to select reliable partners, monitor their reputation, and punish cheaters. In the within group tug of war model [39] , each individual selfishly expends some fraction of the total group output ("communal pie") to increase its share of that output. This selfish fraction expended for the within group competition is called the "selfish effort." An indi vidual's share in the tug of war ("slice of communal pie") depends on the individual's selfish effort in the tug of war relative to the summed selfish efforts of other group members. The model of the between group tug of war relationships is based on the same principles, which creates a two tiered, nested tug of war competition. The more energy is expended by individuals in the within group competition, the less energy remains for the between group tug of war, and the less is the size of the "communal pie". Studying this model using the game theory confirmed that the between group competition (manifested in this case as the decrease in the individual selfish efforts) should increase with the increase in the degree of the within group kinship (which is in complete agreement with the theory of kin selection). However, the model demonstrated that if the competition between the groups is intense, cooperation could exist even in the case of very low degree of kinship between the group members. Intergroup competition is one of the main factors stimulating development of cooperation and altruism in social organisms [39] . Darwin was the first to suggest an association between the evolution of altruism and inter group competition [40] . Later, this theory was applied to social insects. Nothing brings community closer together than joint confrontation with other communities; this is a very reliable strategy for building an altruistic "anthill" [39] . Mathematical modeling supported the idea that in humans, altruism towards members of one's own group could develop only in combination with the development of parochialism (hostility to strangers) [41, 42] , as it has occurred in multiple intergroup conflicts. According to Bowles [42] , tribes of our ancestors feuded between themselves and had strong kinship within the tribes, which could facilitate the development of altruism in the groups due to natural selection. Bowles demonstrated that the level of altruism development depends on four parameters: (i) intensity of intergroup conflicts, which can be evaluated based on the number of war related deaths; (ii) effect of the increase in the fraction of altru ists (for example, soldiers ready to die for their tribe) on the probability of winning in the intergroup conflict; (iii) how much higher is the degree of kinship within the group than the kinship between the groups; and (iv) group size. According to the calculations, selection in the society of primitive hunter-gatherers should favor intragroup altru ism at a high level with the corresponding decrease in the individual adaptation of altruists by 2 3%. In other words, an altruistic gene could spread in the population even if the chance to survive and reproduce of the carriers of this gene was 2 3% lower than for the egoistic tribesmen. Bowles presented two following calculations. If the initial allele frequency in the population is 90%, and the repro ductive success of the carrier of this allele is by 3% lower than of the carriers of other alleles, the frequency of the "harmful" allele will decrease from 90 to 10% already after 150 generations. Hence, from the natural selection point of view, reduction in adaptability by 3% is critical. If the same value (3%) will be considered from the "mili tary" point of view, then in order to keep the degree of altruism at the level of 0.03, the death toll in military con flicts must be more than 20% (taking into account the fre quency and severity of Paleo wars). This means that in the case of serious war conflicts, every fifth altruist must sac rifice his life for the common victory [42] . Hence, it is likely that such opposite human qualities as kindness and aggressiveness have developed simultane ously [43] . It was established that among 3 to 6 year old children, only 5% are selfless altruists. This value grows with age, holding back the development of social para sitism [43] . These features of child psychology are prod ucts of both biological (genes) and social (upbringing) evolution. For example, a new behavioral attribute could initially be passed from generation to generation through education and imitation (similarly to the process occur ring in ants and many other animals) and then will be gradually be incorporated into the genes (Baldwin effect) [44] . Natural selection in the evolution of social animals results in the development of various predominant forms of social and reproductive behavior. For example, rodents can live in small and large groups, be more acceptive or aggressive toward their relatives (including newborns), and either form or not form relationship with other mem ber of the group (including breeding partners). Any of these behavioral adaptations could promote adaptation to certain environmental conditions, but could also require compromises, such as communal use of resources, higher parental investment, increased risk to become a victim of a predator, and others [45] . Any communities -primitive anonymous communities or highly developed personal ized communities in which all members know each other from personal experience -can facilitate adaptation and be supported by selection. The lifespan of social animals is usually longer than of their single counterparts. The pinnacle of sociality evolution is eusociality. Most researchers [46 49 ] define eusociality as an adaptation to communal living in the same nest inhabited by adult indi viduals when (i) they are represented by at least two gen erations, (ii) they cooperate in performing various tasks, and (iii) have particular reproductive functions (existence of casts). Eusociality is widespread among Hymenoptera (ants, bees, Vespidae and Sphecidae wasps) and termites. In each of these groups, social life has emerged inde pendently. Communities of these insects are personal ized. For example, northern paper wasps (Polistes fusca tus) recognize each other by facial patterns [50, 51] . It has been assumed previously [52] that eusociality in insects could develop as either a parasocial phenome non (voluntary association of individuals into community that develops more complex care of the offspring), or sub social phenomenon (development and increase of com plexity of parental behavior). In reality, the parasocial pathway is unlikely to exist, because firstly, there are no known species whose colonies end their development without transitioning to the mother-daughter relation ship [53] . At the same time, eusociality development through the subsocial pathway has been demonstrated for all studied bee and wasp species. The emergence of non productive cast in the mother-daughter societies only is also postulated by the haplodiploidy hypothesis. According to this theory, due to the haplodiploid sex determination in Hymenoptera, sisters become more close relatives than mothers and daughters, and, hence, according to the Hamilton's rule, it is more profitable for an individual to take care of sisters than to produce its own daughters. Moreover, it has been shown that even a high degree of genetic relationship between the workers in the nest is often insufficient for "reasonable selfishness", i.e., voluntary refusal of workers to lay their own eggs. It is likely that this mechanism is maintained more efficiently, when strict "police measures" are implemented (such as destruction of "illegal" eggs by other workers) [53] . Mechanisms for the maintenance (regulation) of altruism. After altruism has emerged, it should be main tained, which is hindered by cheaters. In order to survive, species with a high proportion of altruists should protect themselves from "free riders" (cheaters). The presence of egoists makes the emergence of mutations providing pro tection from them very likely. In the social amoeba Dictyostelium, this results in the evolutionary arm race between the cheaters and "noble" amoebas [54] . Experiments in genetics and selection have allowed to produce mutant amoebas that were securely protected from the cheaters due to the emerged protective mutation (although not from all cheaters, but only from those they competed with in the experiment). Moreover, the mutants protected both from cheaters themselves and other noble amoebas if the latter were present. These experiments were repeated many times, and every time, one or another strain of amoebas developed mutations responsible for the emerging resistance, although these mutations were in different genes and determined differ ent resistance mechanisms in each case. In the process, some cheater resistant strains became cheaters them selves towards the "wild" amoebas, while the other remained noble [54] . A single mutation in the Mixococcus bacteria in one of the regulatory genes affecting bacteria behavior trans formed cheaters into cheater resistant altruists [55] . In yeast, "peaceful co existence" of altruists (pro ducers of commonly beneficial product invertase, an enzyme cleaving sucrose into glucose and fructose) with cheaters (yeast cells that do not synthesize invertase, but consume glucose produced by other community mem bers) is ensured by a small advantage received by the altruists in the presence of very low glucose concentra tions in the medium, as well as by the special non linear dependence of yeast proliferation on the amount of avail able nutrients. Around 1% of the monosaccharides pro duced by altruists are consumed by altruists themselves; hence, if the content of altruists in the mixed population is very low, it becomes more beneficial to produce inver tase than not to do this [56] . It is likely that the evolution of social bacteria and Protozoa has shifted many times towards the formation of multicellular organism. However, no real multicellular organisms had formed in the course of evolution from social bacteria or Protozoa (only plasmodia and fruiting bodies). One of the reasons for the evolutionary futility of the multicellular organism formation from associations of single cell individuals is the fact that such associations provide ideal conditions for the development of social parasitism. Any mutation that provides a single cell indi vidual with the ability to use advantages of living in a mul ticellular community without contributing to it in return has the chance for spreading despite its disastrous conse quences for the community. The mechanism of altruism maintenance through improving the reputation of an altruist ("indirect reci procity") is realized in humans through verbal communi cation -the most ancient way of spreading compromis ing information about the unreliable members of the community, which facilitates team building and punish ment of egoists [57] . Interestingly, Arabian babblers (Turdoides squamiceps) compete for the possibility to per form "good deeds" (acting as sentinels, helping to take care of chicks, feeding other adult birds), because it improves their social status. In other words, these birds have an institution similar to human reputation [58] . Possible mechanisms of phenoptosis development. In a wider sense, phenoptosis is a programmed death that often develops as an adaptive (benefiting descendants) death [7, 59, 60] . Based on the latest data [6 8], we can say with confidence that adaptive death exists in many groups of organisms, from unicellular ones to vertebrates. The question remains open whether phenoptosis could have developed in the course of evolution if it does not provide any benefits to the community. Adaptive death increases combined (inclusive) adaptation, i.e., the effi ciency of the individual's gene transfer to the next gener ation independently on the carrier of gene copies (indi vidual's offspring or relatives) [6] . Colonial unicellular organisms (Saccharomyces cere visiae yeast), demonstrate the type of adaptive death of named "biomass sacrifice" [6] . As the availability of nutrients in the aging yeast colonies decreases, some cells in the colony center undergo programmed death [60 62] . Another variant of adaptive death recognized by Galimov and Gems [8] as consumer sacrifice was described in detail for a number of bacteria in [63, 64] . BIOCHEMISTRY (Moscow) Vol. 86 Nos. 12 13 2021 For example, individual cells of Myxococcus xantus die in order to stop to consume nutrients, which increases the availability of these nutrients for the relatives [65] . Some cells in Bacillus subtilis biofilms form spores and continue to grow using alternative metabolites [66] . Sporulating cells produce cannibalistic toxins, which kill their non sporulating relatives. Streptococcus pneumoniae bacteria acquire ability (competence) to absorb exogenous DNA and produce bacteriocins that selectively kill non compe tent cells [64, 66, 67] . The mechanisms of adaptive death have been investigated by Galimov and Gems [8] in the free living nematode Caenorhabditis elegans [6, 68] . Adult C. elegans are hermaphrodites that first produce spermatozoa and then oocytes. The resulting limitation of the number of spermatozoa results in the cessation of reproduction already 2 3 days after the worm reaches its reproductive maturity, which potentially facilitates evolu tion of adaptive death [6] . Furthermore, significant age related reduction in the consumption rate in C. elegans increases the availability of food for the relatives [69] . Galimov and Gems [8] used modeling to demonstrate that in the case of high reproductivity, shorter reproduc tive period and shorter lifespan increase the colony adap tivity by decreasing nonproductive food consumption in the population. In general, adaptive death develops easier in the organisms subjected to reproductive death: early termina tion or slowdown of reproduction (for any reason) create premises for the evolution of phenoptosis [6, 70] . One of the known examples of reproduction associated altruistic behavior is observed in the representatives of Mantises order (for example, in Miomantis caffra). In this case, self sacrifice of males is probably the best strategy. Males that are ready to sacrifice their life have received the advantage in the course of natural selection. Mantis male is an ideal food for the fertilized female, which can pro vide sufficient amount of protein for the entire pregnan cy, thus improving the chances for procreation. It was found that the amount of nutrients in the eggs from females that ate their males was 3 fold higher than when the male partner remained alive. Therefore, mantises devour their males for the sake of providing future proge ny with protein. However, this behavioral response is not absolutely determined and allows variations -in half of the cases male mantises manage to avoid death [71] . Some spider males really "want" to be eaten and plunge themselves into female chelicera. This is observed for spider species (for example, Argiope bruennichi) in which the number of small males is significantly higher than the number of large females, i.e., an individual male has virtually no chance for repeated mating even if it remains alive [72] . The synthesis of catecholamines and neuropeptides responsible for feeding behavior drops drastically in the tissues of optic glands of the California two spot octopus (Octopus bimaculoides) females in the course of reproduc tive cycle (when females care for eggs). Simultaneously, the synthesis of steroids involved in the metabolism of cholesterol and insulin increases in the optic gland [48] . These results contradict the hypothesis of a single "self destruct hormone" implying that the programmed death of female octopus is associated with complex changes of its hormonal status (i.e., operation of Master Biological Clock, in fact) [48] . Similar phenomenon has been observed in mammals. Male pouched mice (Antechinus) experience severe hormonal disbalance during the mating period that results in their death at the end of mating peri od [73] . It was supposed [5] that adaptive aging (and adaptive death) could develop in the colonial viscous (non dis persed) populations under two conditions: (i) high viscos ity (low intermixing), which guarantees a high probabili ty that resources freed by the death of an individual will be inherited by the offspring and relatives; (ii) relatively early and fast reduction of reproduction (as in C. elegans). Pacific salmon (Oncorhynchus nerka) is known by its abil ity to return in large numbers (from 73 to 98%) to the creeks of its birthplace. Moreover, local salmon popula tions are not panmictic, but exist as metapopulations with a hierarchic structure [74] . This means that Pacific salmon that return to the creeks to spawn have a high degree of kinship, which likely guarantees that all benefits of paternal biomass sacrifice would be available to the rel atives. A similar pattern of death after spawning has been described for the lampreys [75] . Adaptive death is a form of extreme altruism, which is likely limited to the organ isms demonstrating such a high degree of kinship, social structure, and physical association that they acquire the features typical for a higher order of organization (e.g., formation of colonies of unicellular organisms that share some features with multicellular organisms or colonies of multicellular animals with some supra organ ism features). This is a part of a wider phenomenon, when adaptation at the colony level increases at the expense of adaptation loss at the individual level. Another mechanism of the emergence of phenopto sis is associated with the limits of brain hyperdevelopment and behavioral models in humans. In human society, bio logical evolution has turned its back to the cultural evolu tion. As discussed in the recent review [32] , genetic cul tural evolution in humans can not only limit brain devel opment, but can also facilitate counterproductive process -support brain degradation (intellectual stagna tion or decrease in IQ). This occurs when reproductive success of an individual becomes independent on the advantage of this individual in the competition for resources (or when at a certain stage of cultural and social development, individuals with lower cognitive abilities become more competitive). And if the success in life is not converted into the reproductive success, the cultural drive cease to work (or works in the opposite direction: the worse, the better) [32] . BIOCHEMISTRY (Moscow) Vol. 86 Nos. 12 13 2021 Effect of type of selection on the adaptive death and aging. The existence of adaptive death in clonal popula tions could be explained by kin selection (aiming at the preservation of features that favor survival of close rela tives), because clonal colonies could be considered as "super organisms". As mentioned above, according to the Hamilton's rule, natural selection can promote altru istic behavior when nrB > C, where r is relatedness; B is the benefit of the recipient; n is the number of recipients, and C is the cost for the altruist [76] . If the coefficient of relatedness r = 1, the Hamilton's rule nrB > C is simpli fied to nB > C, and it becomes easier to meet its require ments. The cost (C) of death of an individual is over weighed by the benefits (B) for multiple relatives. Travis [70] used computer modeling to demonstrate that it could also be true for spatially structured populations with a high proportion of older individuals. The main requirement for the kin selection to work in the Travis model is low dispersal as a condition for the "inheritance of resources" (transfer of resources from dying individu als to their relatives) [8] . This requirement is met in the colonies of bacteria and even C. elegans. Similar results have been reported by Markov [5] . Adaptive death develops easier in the organisms sub jected to reproductive death [6, 70] . Similar to salmon, hermaphroditic C. elegans nematodes experience repro ductive death [6, 8] . This could reflect the co evolution of two features predicted by the Hamilton's rule. Individual adaptation of semelparous organisms (organisms that reproduce only once in life) becomes negligibly low after the reproduction episode. This means that the adaptive death either causes an insignificant decrease in the indi vidual adaptation (C) or does not decrease it at all, while potential benefits for other individuals (B) remain. Similar notions have been used recently for explaining the evolution of mass suicide of Escherichia coli cells [6, 77] . Hence, adaptive death is plausible in organisms that are not clonal or colonial. The majority of biological populations are arranged into classes (according to sex, age, cast, etc.); hence, adaptation of a social group could change due to the re arrangement of classes, i.e., not be directly associated with genes and natural selection [8, 78 81] . As mentioned above, evolutionary benefits of adap tive death would be more pronounced if a significant por tion of the population is old [82] . Stress conditions could accelerate aging (one of the aging programs is induced by the mitochondrial reactive oxygen species, ROS) by reducing the reproductive function and, hence, increas ing the benefits of the adaptive death [83] . Aging has also been investigated from the point of view of multilevel selection [5, 70, 84] . The effect of the decrease in the force of natural selection with the individ ual's age on the evolution of aging was described mathe matically for idealized (i.e., dispersed and interconnect ed) Wright-Fisher populations without taking into account social and ecological factors, such as spatial structure, availability of resources, or dispersion [85, 86] . Lohr et al. [6] demonstrated how the death of an organ ism in the course of cell aging could evolve as an adaptive group feature in species existing as populations with a high degree of kinship (especially for the populations of clones) and low level of dispersion. Each particular species has the maximal recorded LS value. It is still unclear whether the LS limit is supported by selection directly (i.e., if it is an adaptation) or this is a side effect of selection based on other features that increase adaptability. Identification of LS increasing mutations implies that aging is under control of genes, while evolutionary forces limiting LS have not been elu cidated yet. The model developed by Lidsky and Andino [87] demonstrated that limitations of LS are beneficial for the fight against epidemics and provided possible explanation for the selection of particular LS values and the absence of immortal mutants. Their hypothesis states that selec tion for the LS control prevents in part and limits the out breaks of chronic infections. Populations migrate often to colonize new habitats or just encounter factors that can significantly decrease the population density. The authors investigated the correlation between the pre determined LS and pathogen load in the case of host migration to another habitat, including reduction of the population size, or population "bottleneck". In particular, they demonstrated that the infected founders in the popula tions with a shorter LS would die before the population density reaches the level facilitating fast pathogen trans mission. Respectively, shorter LS limits the spread of infection and accelerates elimination of pathogens in comparison with the populations with a longer LS [87] . Limitation of LS is especially beneficial in the context of transmission of zoonotic pathogens, which requires their adaptation to a new host. We believe that infection out breaks can promote control of the evolutionary deter mined LS values for species. In many cases, altruism provides certain benefits for adaptation, which is undoubtedly proven by the variety of mechanisms of its emergence (figure). There are at least two global mechanisms of altruism emergence. In the first one (induced), an individual becomes altruistic when affected by environmental fac tors without undergoing any internal changes, i.e., pas sively. Such factors could originate from changes occur ring in other individuals (for example, cheaters). In the second mechanism, an individual become altruistic due to changes in its own behavior. For example, the right for reproduction in a community is preferentially given to the highly ranked individuals, while the low rank individuals BIOCHEMISTRY (Moscow) Vol. 86 Nos. 12 13 2021 are assigned an altruistic role of "service personnel". In the majority of highly organized communities, altruists do not appear randomly, but are rather appointed. In the limiting cases (eusocial communities), the inequality is established genetically. The emergence of such inequality in the course of evolution could be seen in ants: gamer gates (working ants capable of reproduction) exist in more primitive ant species, but not in more evolutionary developed ones [88] . Another example of the second mechanism of altruism emergence as a result of group selection and Simpson's paradox is adaptive death (usual ly, acute phenoptosis) as a form of acute altruism (see dis cussion in this article). Phenoptosis as an altruistic program. At first glance, emergence of phenoptosis in the course of evolution seems paradoxical. Longevity per se is not the primary evolutionary goal of living organisms. From the evolu tionary point of view, the priority is adaptation to envi ronmental conditions linked to the need for survival, food supply, and reproduction. Regulation of homeostasis and organism repair comprise a complex network of intercon nected reactions, the efficiency of which decreases with age. Both known types of phenoptosis (chronic and acute) have adaptive significance [89] , while acute phenoptosis is primarily associated with the (excessive) response to abrupt action of external factors (such as infection). On the other hand, chronic phenoptosis is associated with the action of internal factors, with opti mization of LS as a species trait (such as height, size, mass, etc.). Hence, we can see a broad diversity of types of pro grammed death in nature, especially if it is associated with reproduction. At the same time, such death is not always altruistic. When environmental conditions change abruptly, species with the highest plasticity of phenotypic (includ ing behavioral) features, which are capable to alter as fast as the environment, have an advantage over species most adapted to the external conditions. As mentioned above, this is the main characteristic of counterproductive pro grams (ability to respond to the cue very fast independ ently on its harmfulness). It is likely that on the evolu tionary timescale, such feature helps its carriers rather than interferes with their existence. In particular, it would be useful for passing through the evolutionary bottlenecks (sharp reductions in the population size due to natural disasters or epidemics). Even in the history of humans, who are famous for their adaptability, there had been at least three bottlenecks, when the size of human popula tion decreased to several tens of thousands of people [90] . Exposure to infectious agents (such as malaria agent) reveals a wide spectrum of genetic diversity, which under lies the variability in the susceptibility to infectious dis eases and their complications [91] . Moreover, the adap tive value of a feature could change due to the changes in lifestyle. Therefore, the capacity for the super strong response, which had been beneficial for Stone Age humans, likely became less adaptive recently. In particu lar, the immune system of the first farmers had become weaker during transition from the hunter-gatherer lifestyle to agriculture in order to prevent induction of the cytokine storm that could kill the infected individu als [92] . Deaths caused by the COVID 19 pandemic as phenoptosis with altruistic goals. At the early stages of human evolution, when human populations were scat tered to the same extent as present population of other large animals, programmed death helped to overcome diseases (and prevent their spread over large areas) via rapid death of disease carriers (e.g., sepsis or diseases, such as plague, cholera, etc.). Infected individuals died because of the induced internal program, as well as due to the exclusion from the society (as communities tried to steer clear from sick people). One of the new recent examples are minks in Denmark. When the COVID 19 virus was discovered in a small population of minks, it was suggested to kill them all, which solves the problem from the evolutionary point of view. According to the data on 23 large pandemics and epidemics, COVID 19 is not in the top ten of most deadly epidemics (for this, the num ber of victims should reach 38.5 million people, and to be in the first five -up to 210 million). The deadliest disease in the human history was plague that took the life of 200 million people in 1347 1351 A.D. (∼42% of the world population at that time). The number of deaths during the plague epidemics in 541 542 A.D. was 60 million people (28.5% of the world population) [93, 94] . The deadliest infectious disease is currently HIV/AIDS. Infection with human immunodeficiency virus has caused the death of 30 million people since the discovery of this disease in 1981. The outbreaks of severe acute respiratory syndrome (SARS), Middle East respira tory syndrome, and influenza virus H1N1 had happened in the early 2000s. In most recent pandemics, the virus was transmitted to humans from animals. All coron aviruses -SARS, MERS, and COVID 19 -had been transmitted to humans from bats [95] . A serious question remains unanswered on whether SARS CoV 2 will continue to circulate in the human population or could it be eradicated by vaccinations and anti epidemic measures. According to the optimistic forecasts, the pandemics should end after a year of mas sive and effective vaccination. However, it has become clear that vaccination of 75% of population is impossible due to social issues. Even more so is vaccination of 90% of population, which seems unachievable. The situation is complicated by the fast emerging new mutant variants. According to Wenzel [96] , the outbreaks of viral infections are natural life events. Although the time of disease outbreak and the severity of viral infection are unpredictable, the spread of the disease will eventually come down. In our opinion, it is important to search for the ways to reduce the intensity of organism's excessive and potentially lethal response. Such hyper response is a powerful evolutionary acquisition that allows the body to adapt to acute changes in living conditions. In essence, one of the most ancient prototypes of such lethality is the well known phenomenon of quorum sensing, when trig gering a process that significantly affects the fate of the entire population is beyond the capacities of a single indi vidual, but becomes possible, when the size of population reaches a certain threshold. Based on the data presented in this work, if death of a fraction of the population pre vents further spread of infection, it is an altruistic event. In some cases, aging can also have adaptive significance. Sometimes, phenoptosis is a continuation of the develop ment programs, as for instance, the mechanism of Nrf2 inhibition by glycogen synthase kinase GSK3β, including via induction of inflammaging [97, 98] . Some of the promising agents are antioxidant preparations targeting different metabolic processes, e.g., those preventing cytokine storm [99] , both traditional (plant extracts [100] and active components of blood serum [101] ) and derived, for example, from insects [102] . The most prom ising at the moment are the main antioxidant of the body, glutathione [103] , and, in addition, artificially synthe sized antioxidants [103] , such as the mitochondria directed SkQ ions [104] . It was shown recently that the death of mice caused by administration of lipopolysac charides, intravenous administration of mitochondria, and exposure to cold or toxic shock could be prevented by application of Skulachev ions (SkQ) [104] . 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From correlation to causation: analysis of metabolomics data using systems biology approaches Acknowledgments. The authors express their grati tude to Professor V. P. Skulachev for the original idea and valuable advice and help in writing this review. The authors are grateful to E. R. Galimov for helpful advice and comments.Funding. This work was supported by the Russian Foundation for Basic Research (project no. 18 29 13037).