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The review discusses the role of metabolic disorders (in particular, insulin resistance) in the development of age-related diseases and normal aging with special emphasis on the changes in postmitotic cells of higher organisms. Caloric restriction helps to prevent such metabolic disorders, which could probably explain its ability to prolong the lifespan of laboratory animals. Maintaining metabolic homeostasis is especially important for the highly differentiated long-lived body cells, whose lifespan is comparable to the lifespan of the organism itself. Normal functioning of these cells can be ensured only upon correct functioning of the cytoplasm clean-up system and availability of all required nutrients and energy sources. One of the central problems in gerontology is the age-related disruption of glucose metabolism leading to obesity, diabetes, metabolic syndrome, and other related pathologies. Along with the adipose tissue, skeletal muscles are the main consumers of insulin; hence the physical activity of muscles, which supports their energy metabolism, delays the onset of insulin resistance. Insulin resistance disrupts the metabolism of cardiomyocytes, so that they fail to utilize the nutrients to perform their functions even being surrounded by a nutrient-rich environment, which contributes to the development of age-related cardiovascular diseases. Metabolic pathologies also alter the nutrient sensitivity of neurons, thus disrupting the action of insulin in the central nervous system. In addition, there is evidence that neurons can develop insulin resistance as well. It has been suggested that affecting nutritional sensors (e.g., AMPK) in postmitotic cells might improve the state of the entire multicellular organism, slow down its aging, and increase the lifespan.

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.

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.

An original bioinformatics technique is developed to identify the protein-coding genes in rodents, lagomorphs and nonhuman primates that are pseudogenized in humans. The method is based on per-gene verification of local synteny, similarity of exon-intronic structures and orthology in a set of genomes. It is applicable to any genome set, even with the number of genomes exceeding 100, and efficiently implemented using fast computer software. Only 50 evolutionary recent human pseudogenes were predicted. Their functional homologs in model species are often associated with the immune system or digestion and mainly express in the testes. According to current evidence, knockout of most of these genes leads to an abnormal phenotype. Some genes were pseudogenized or lost independently in human and nonhuman hominoids.

We have developed an efficient algorithm implemented in a program for a multiprocessor computing system, which makes it possible to discover genes lost or acquired during the evolution of most species from a given set. The new approach takes into account the mutual arrangement of genes on a chromosome and allows us to simultaneously consider hundreds of species. The research was carried out using supercomputers at the Joint Supercomputer Center of the Russian Academy of Sciences (JSCC RAS).

Measurements of variation are of great importance for studying the stability of pathological phenomena and processes. For the biology of aging, it is very important not only to determine average mortality, but also to study its stability in time and the size of fluctuations that are indicated by the variation coefficient of lifespan (CVLS). It is believed that a relatively small (~20%) value of CVLS in humans, comparable to the coefficients of variation of other events programmed in ontogenesis (for example, menarche and menopause), indicates a relatively rigid determinism (N. S. Gavrilova et al. (2012) Biochemistry (Moscow), 77, 754-760). To assess the prevalence of this phenomenon, we studied the magnitude of CVLS, as well as the coefficients of skewness and kurtosis in diverse representatives of the animal kingdom using data provided by the Institute for Demographic Research (O. R. Jones et al. (2014) Nature, 505, 169-173). We found that, unlike humans and laboratory animals, in most examined species the values of CVLS are rather high, indicating heterogeneity of the lifespan in the cohorts studied. This is probably due to the large influence of background mortality, as well as the non-monotonicity of total mortality in the wild, especially at the earliest ages. One way to account for this influence is to "truncate" the data (removing the earliest and latest ages from consideration). To reveal the effect of this procedure, we proposed a new indicator, the stability coefficient of mortality dynamics, which indicates how quickly CVLS is reduced to values that characterize a relatively homogeneous population (33%) when the data are "truncated". Such indicators facilitate the use of the parameters of survival curves for analysis of the effects of geroprotectors, lifestyle, and other factors on lifespan, and for the quantification of relative contributions of genetic and environmental factors to the dynamics of aging in human and animal populations, including those living in the wild.

Age-related dysfunctions are accompanied by impairments in the mitochondrial morphology, activity of signaling pathway, and protein interactions. Cardiolipin is one of the most important phospholipids that maintains the curvature of the cristae and facilitates assembly and interaction of complexes and supercomplexes of the mitochondrial respiratory chain. The fatty acid composition of cardiolipin influences the biophysical properties of the membrane and, therefore, is crucial for the mitochondrial bioenergetics. The presence of unsaturated fatty acids in cardiolipin is the reason of its susceptibility to oxidative damage. Damaged cardiolipin undergoes remodeling by phospholipases, acyltransferases, and transacylases, creating a highly specific fatty acyl profile for each tissue. In this review, we discuss the variability of cardiolipin fatty acid composition in various species and different tissues of the same species, both in the norm and at various pathologies (e.g., age-related diseases, oxidative and traumatic stresses, knockouts/knockdowns of enzymes of the cardiolipin synthesis pathway). Progressive pathologies, including age-related ones, are accompanied by cardiolipin depletion and decrease in the efficiency of its remodeling, as well as the activation of an alternative way of pathological remodeling, which causes replacement of cardiolipin fatty acids with polyunsaturated ones (e.g., arachidonic or docosahexaenoic acids). Drugs or special diet can contribute to the partial restoration of the cardiolipin acyl profile to the one rich in fatty acids characteristic of an intact organ or tissue, thereby correcting the consequences of pathological or insufficient cardiolipin remodeling. In this regard, an urgent task of biomedicine is to study the mechanism of action of mitochondria-targeted antioxidants effective in the treatment of age-related pathologies and capable of accumulating not only in vitro, but also in vivo in the cardiolipin-enriched membrane fragments.

Background Gerontogenes include those that modulate life expectancy in various species and may be the actual longevity genes. We believe that a long (relative to body weight) lifespan in individual rodent and primate species can be due, among other things, to the loss of particular genes that are present in short-lived species of the same orders. These genes can also explain the widely different rates of aging among diverse species as well as why similarly sized rodents or primates sometimes have anomalous life expectancies (e.g., naked mole-rats and humans). Here, we consider the gene loss in the context of the prediction of Williams’ theory that concerns the reallocation of physiological resources of an organism between active reproduction (r-strategy) and self-maintenance (K-strategy). We have identified such lost genes using an original computer-aided approach; the software considers the loss of a gene as disruptions in gene orthology, local gene synteny or both. Results A method and software identifying the genes that are absent from a predefined set of species but present in another predefined set of species are suggested. Examples of such pairs of sets include long-lived vs short-lived, homeothermic vs poikilothermic, amniotic vs anamniotic, aquatic vs terrestrial, and neotenic vs nonneotenic species, among others. Species are included in one of two sets according to the property of interest, such as longevity or homeothermy. The program is universal towards these pairs, i.e., towards the underlying property, although the sets should include species with quality genome assemblies. Here, the proposed method was applied to study the longevity of Euarchontoglires species. It largely predicted genes that are highly expressed in the testis, epididymis, uterus, mammary glands, and the vomeronasal and other reproduction-related organs. This agrees with Williams’ theory that hypothesizes a species transition from r-strategy to K-strategy. For instance, the method predicts the mouse gene Smpd5, which has an expression level 20 times greater in the testis than in organs unrelated to reproduction as experimentally demonstrated elsewhere. At the same time, its paralog Smpd3 is not predicted by the program and is widely expressed in many organs not specifically related to reproduction. Conclusions The method and program, which were applied here to screen for gene losses that can accompany increased lifespan, were also applied to study reduced regenerative capacity and development of the telencephalon, neoteny, etc. Some of these results have been carefully tested experimentally. Therefore, we assume that the method is widely applicable.

Social insects with identical genotype that form castes with radically different lifespans are a promising model system for studying the mechanisms underlying longevity. The main direction of progressive evolution of social insects, in particular, ants, is the development of the social way of life inextricably linked with the increase in the colony size. Only in a large colony, it is possible to have a developed polyethism, create large food reserves, and actively regulate the nest microclimate. The lifespan of ants hugely varies among genetically similar queens, workers (unproductive females), and males. The main advantage of studies on insects is the determinism of ontogenetic processes, with a single genome leading to completely different lifespans in different castes. This high degree of determinacy is precisely the reason why some researchers (incorrectly) call a colony of ants the "superorganism", emphasizing the fact that during the development, depending on the community needs, ants can switch their ontogenetic programs, which influences their social roles, ability to learn (i.e., the brain [mushroom-like body] plasticity), and, respectively, the spectrum of tasks performed by a given individual. It has been shown that in many types of food behavior, older ants surpass young ones in both performing the tasks and transferring the experience. The balance between the need to reduce the "cost" of non-breeding individuals (short lifespan and small size of workers) and the benefit from experienced long-lived workers possessing useful skills (large size and "non-aging") apparently determines the differences in the lifespan and aging rate of workers in different species of ants. A large spectrum of rigidly determined ontogenetic trajectories in different castes with identical genomes and the possibility of comparison between "evolutionarily advanced" and "primitive" subfamilies (e.g., Formicinae and Ponerinae) make ants an attractive object in the studies of both normal aging and effects of anti-aging drugs.

Accumulation of various types of lesions in the course of aging increases an organism's vulnerability and results in a monotonous elevation of mortality rate, irrespective of the position of a species on the evolutionary tree. Stroustrup et al. (Nature, 530, 103-107) [1] showed in 2016 that in the nematode Caenorhabditis elegans, longevity-altering factors (e.g. oxidative stress, temperature, or diet) do not change the shape of the survival curve, but either stretch or shrink it along the time axis, which the authors attributed to the existence of an "aging program". Modification of the accelerated failure time model by Stroustrup et al. uses temporal scaling as a basic approach for distinguishing between quantitative and qualitative changes in aging dynamics. Thus we analyzed data on the effects of various longevity-increasing genetic manipulations in flies, worms, and mice and used several models to choose a theory that would best fit the experimental results. The possibility to identify the moment of switch from a mortality-governing pathway to some other pathways might be useful for testing geroprotective drugs. In this work, we discuss this and other aspects of temporal scaling.

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.

Accumulation of various types of unrepaired damage of the genome because of increasing production of reactive oxygen species and decreasing efficiency of the antioxidant defense system and repair systems can cause age-related diseases and emergence of phenotypic signs of senescence. This should lead to increasing vulnerability and to mortality monotonously increasing with age independently of the position of the species on the evolutionary tree. In this light, the survival, mortality, and fertility curves for 45 animal and plant species and one alga published by the Max Planck Institute for Demographic Research (Germany/Denmark) are of special interest (Jones, O. R., et al. (2014) Nature, 505, 169-173). We divided all species treated in that study into four groups according to the ratio of mortality at the terminal age (which corresponds to 5% survival) and average mortality during the entire studied period. For animals of group IV (long-lived and senescent), including humans, the Jones method makes it possible to trace mortality during the entire life cycle. The same applies to short-lived animals (e.g. nematodes or the tundra vole), whether they display the Gompertz type of senescence or not. However, in long-lived species with a less pronounced increase in mortality with age (e.g. the freshwater crocodile, hermit crab, or Scots pine), as well as in animals of average lifespan that reach the terminal age earlier than they could have enough time to become senescent, the Jones method is capable of characterizing only a small part of the life cycle and does not allow judging how senescence manifests itself at late stages of the life cycle. Thus, it is known that old trees display signs of biological senescence rather clearly; although Jones et al. consider them non-senescent organisms because less than 5% of sexually mature individuals survive to display the first manifestations of these characters. We have concluded that the classification proposed by Jones et al. makes it possible to approximately divide animals and plants only by their levels of the Gompertz type of senescence (i.e. actuarial senescence), whereas susceptibility to biological senescence can be estimated only when principally different models are applied.

It is well known that the number of dividing cells in an organism decreases with age. The average rate of cell division in tissues and organs of a mature organism sharply decreases, which is probably a trigger for accumulation of damage leading to disturbance of genome integrity. This can be a cause for the development of many age-related diseases and appearance of phenotypic and physiological signs of aging. In this connection, the protein poly(ADP-ribosyl)ation system, which is activated in response to appearance of various DNA damage, attracts great interest. This review summarizes and analyzes data on changes in the poly(ADP-ribosyl)ation system during development and aging in vivo and in vitro, and due to restriction of cell proliferation. Special attention is given to methodological aspects of determination of activity of poly(ADP-ribose) polymerases (PARPs). Analysis of relevant publications and our own data has led us to the conclusion that PARP activity upon the addition of free DNA ends (in this review referred to as stimulated PARP activity) is steadily decreasing with age. However, the dynamics of PARP activity measured without additional activation of the enzyme (in this review referred to as unstimulated activity) does not have such a clear trend: in many studies, the presented differences are statistically non-significant, although it is well known that the number of unrepaired DNA lesions steadily increases with aging. Apparently, the cell has additional regulatory systems that limit its own capability of reacting to DNA damage. Special attention is given to the influence of the cell proliferative status on PARP activity. We have systematized and analyzed data on changes in PARP activity during development and aging of an organism, as well as data on differences in the dynamics of this activity in the presence/absence of additional stimulation and on cellular processes that are associated with activation of these enzymes. Moreover, data obtained in different models of cellular aging are compared.

In most mammals, involution of the thymus occurs with aging. In this issue of Biochemistry (Moscow) devoted to phenoptosis, A. V. Khalyavkin considered involution of a thymus as an example of the program of development and further--of proliferation control and prevention of tumor growth. However, in animals devoid of a thymus (e.g. naked mice), stimulation of carcinogenesis, but not its prevention was observed. In this report, we focus on the involution of the thymus as a manifestation of the aging program (slow phenoptosis). We also consider methods of reversal/arrest of this program at different levels of organization of life (cell, tissue, and organism) including surgical manipulations, hormonal effects, genetic techniques, as well as the use of conventional and mitochondria-targeted antioxidants. We conclude that programmed aging (at least on the model of age-dependent thymic atrophy) can be inhibited.

We believe that cytogerontological models, such as the Hayflick model, though very useful for experimental gerontology, are based only on certain correlations and do not directly apply to the gist of the aging process. Thus, the Hayflick limit concept cannot explain why we age, whereas our “stationary phase aging” model appears to be a “gist model,” since it is based on the hypothesis that the main cause of both various “age-related” changes in stationary cell cultures and similar changes in the cells of aging multicellular organism is the restriction of cell proliferation. The model is applicable to experiments on a wide variety of cultured cells, including normal and transformed animal and human cells, plant cells, bacteria, yeasts, mycoplasmas, etc. The results of relevant studies show that cells in this model die out in accordance with the Gompertz law, which describes exponential increase of the death probability with time. Therefore, the “stationary phase aging” model may prove effective in testing of various geroprotectors (anti-aging factors) and geropromoters (pro-aging factors) in cytogerontological experiments. It should be emphasized, however, that even the results of such experiments do not always agree with the data obtained in vivo and therefore cannot be regarded as final but should be verified in studies on laboratory animals and in clinical trials (provided this complies with ethical principles of human subject research).

The processes that lead to violation of genome integrity are known to increase with age. This phenomenon is caused both by increased production of reactive oxygen species and a decline in the efficiency of antioxidant defense system as well as systems maintaining genome stability. Accumulation of different unrepairable genome damage with age may be the cause of many age-related diseases and the development of phenotypic and physiological signs of aging. It is also clear that there is a close connection between the mechanisms of the maintenance of genome stability, on one hand, and the processes of spontaneous tumor formation and lifespan, on the other. In this regard, the system of protein poly(ADP-ribosyl)ation activated in response to a variety of DNA damage seems to be of particular interest. Data accumulated to date suggest it to be a kind of focal point of cellular processes, guiding the path of cell survival or death depending on the degree of DNA damage. This review summarizes and analyzes data on the involvement of poly(ADP-ribosyl)ation in various mechanisms of DNA repair, its interaction with progeria proteins, and the possible role in the development of spontaneous tumors and lifespan determination. Special attention is given to the relationship between various polymorphisms of the human poly(ADP-ribose) polymerase-1 gene and longevity.