Evolution of Longevity in Tetrapods: Safety Is More Important than Metabolism Level.

Various environmental morphological and behavioral factors can determine the longevity of representatives of various taxa. Long-lived species develop systems aimed at increasing organism stability, defense, and, ultimately, lifespan. Long-lived species to a different extent manifest the factors favoring longevity (gerontological success), such as body size, slow metabolism, activity of body's repair and antioxidant defense systems, resistance to toxic substances and tumorigenesis, and presence of neotenic features. In continuation of our studies of mammals, we investigated the characteristics that distinguish long-lived ectotherms (crocodiles and turtles) and compared them with those of other ectotherms (squamates and amphibians) and endotherms (birds and mammals). We also discussed mathematical indicators used to assess the predisposition to longevity in different species, including standard indicators (mortality rate, maximum lifespan, coefficient of variation of lifespan) and their derivatives. Evolutionary patterns of aging are further explained by the protective phenotypes and life history strategies. We assessed the relationship between the lifespan and various studied factors, such as body size and temperature, encephalization, protection of occupied ecological niches, presence of protective structures (for example, shells and osteoderms), and environmental temperature, and the influence of these factors on the variation of the lifespan as a statistical parameter. Our studies did not confirm the hypothesis on the metabolism level and temperature as the most decisive factors of longevity. It was found that animals protected by shells (e.g., turtles with their exceptional longevity) live longer than species that have poison or lack such protective adaptations. The improvement of defense against external threats in long-lived ectotherms is consistent with the characteristics of long-lived endotherms (for example, naked mole-rats that live in underground tunnels, or bats and birds, whose ability to fly is one of the best defense mechanisms).

Evolution of Longevity as a Species-Specific Trait in Mammals.

From the evolutionary point of view, the priority problem for an individual is not longevity, but adaptation to the environment associated with the need for survival, food supply, and reproduction. We see two main vectors in the evolution of mammals. One is a short lifespan and numerous offspring ensuring reproductive success (r-strategy). The other one is development of valuable skills in order compete successfully (K-strategy). Species with the K-strategy should develop and enhance specific systems (anti-aging programs) aimed at increasing the reliability and adaptability, including lifespan. These systems are signaling cascades that provide cell repair and antioxidant defense. Hence, any arbitrarily selected long-living species should be characterized by manifestation to a different extent of the longevity-favoring traits (e.g., body size, brain development, sociality, activity of body repair and antioxidant defense systems, resistance to xenobiotics and tumor formation, presence of neotenic traits). Hereafter, we will call a set of such traits as the gerontological success of a species. Longevity is not equivalent to the evolutionary or reproductive success. This difference between these phenomena reaches its peak in mammals due to the development of endothermy and cephalization associated with the cerebral cortex expansion, which leads to the upregulated production of oxidative radicals by the mitochondria (and, consequently, accelerated aging), increase in the number of non-dividing differentiated cells, accumulation of the age-related damage in these cells, and development of neurodegenerative diseases. The article presents mathematical indicators used to assess the predisposition to longevity in different species (including the standard mortality rate and basal metabolic rate, as well as their derivatives). The properties of the evolution of mammals (including the differences between modern mammals and their ancestral forms) are also discussed.

Altruism and Phenoptosis as Programs Supported by Evolution.

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.

A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3.

This review discusses genetic and molecular pathways that link circadian timing with metabolism, resulting in the emergence of positive and negative regulatory feedback loops. The Nrf2 pathway is believed to be a component of the anti-aging program responsible for the healthspan and longevity. Nrf2 enables stress adaptation by activating cell antioxidant defense and other metabolic processes via control of expression of over 200 target genes in response to various types of stress. The GSK3 system represents a "regulating valve" that controls fine oscillations in the Nrf2 level, unlike Keap1, which prevents significant changes in the Nrf2 content in the absence of oxidative stress and which is inactivated by the oxidative stress. Furthermore, GSK3 modifies core circadian clock proteins (Bmal1, Clock, Per, Cry, and Rev-erbα). Phosphorylation by GSK3 leads to the inactivation and degradation of circadian rhythm-activating proteins (Bmal1 and Clock) and vice versa to the activation and nuclear translocation of proteins suppressing circadian rhythms (Per and Rev-erbα) with the exception of Cry protein, which is likely to be implicated in the fine tuning of biological clock. Functionally, GSK3 appears to be one of the hubs in the cross-regulation of circadian rhythms and antioxidant defense. Here, we present the data on the crosstalk between the most powerful cell antioxidant mechanism, the Nrf2 system, and the biorhythm-regulating system in mammals, including the impact of GSK3 overexpression and knockout on the Nrf2 signaling. Understanding the interactions between the regulatory cascades linking homeostasis maintenance and cell response to oxidative stress will help in elucidating molecular mechanisms that underlie aging and longevity.

Perspectives of Homo sapiens lifespan extension: focus on external or internal resources?

Homo sapiens and naked mole rats (Heterocephalus glaber) are vivid examples of social mammals that differ from their relatives in particular by an increased lifespan and a large number of neotenic features. An important fact for biogerontology is that the mortality rate of H. glaber (a maximal lifespan of more than 32 years, which is very large for such a small rodent) negligibly grows with age. The same is true for modern people in developed countries below the age of 60. It is important that the juvenilization of traits that separate humans from chimpanzees evolved over thousands of generations and millions of years. Rapid advances in technology resulted in a sharp increase in the life expectancy of human beings during the past 100 years. Currently, the human life expectancy has exceeded 80 years in developed countries. It cannot be excluded that the potential for increasing life expectancy by an improvement in living conditions will be exhausted after a certain period of time. New types of geroprotectors should be developed that protect not only from chronic phenoptosis gradual poisoning of the body with reactive oxygen species (ROS) but also from acute phenoptosis, where strong increase in the level of ROS immediately kills an already aged individual. Geroprotectors might be another anti-aging strategy along with neoteny (a natural physiological phenomenon) and technical progress.

New C-Terminal Conserved Regions of Tafazzin, a Catalyst of Cardiolipin Remodeling.

Cardiolipin interacts with many proteins of the mitochondrial inner membrane and, together with cytochrome C and creatine kinase, activates them. It can be considered as an integrating factor for components of the mitochondrial respiratory chain, which provides for an efficient transfer of electrons and protons. The major, if not the only, factor of cardiolipin maturation is tafazzin. Variations of isoform proportions of this enzyme can cause severe diseases such as Barth syndrome. Using bioinformatic methods, we have found conserved C-terminal regions in many tafazzin isoforms and identified new mammalian species that acquired exon 5 as well as rare occasions of intron retention between exons 8 and 9. The regions in the C-terminal part arise from frameshifts relative to the full-length TAZ transcript after skipping exon 9 or retention of the intron between exons 10 and 11. These modifications demonstrate specific distribution among the orders of mammals. The dependence of the species maximum lifespan, body weight, and mitochondrial metabolic rate on the modifications has been demonstrated. Arguably, unconventional tafazzin isoforms provide for the optimal balance between the increased biochemical activity of mitochondria (resulting from specific environmental or nutritional conditions) and lifespan maintenance; and the functional role of such isoforms is linked to the modification of the primary and secondary structures at their C-termini.