[KE peptide regulates SIRT1, PARP1, PARP2 gene expression and protein synthesis in human mesenchymal stem cells aging.]

It was shown that KE peptide (Lys-Glu, vilon) has immunomodulatory, oncostatic and geroprotective effects. The aim of this work is to evaluate the effect of the KE peptide on gene expression and protein synthesis of SIRT1, PARP1, PARP2 during aging of human mesenchymal stem cells (MSC). The KE peptide increased gene expression and synthesis of the SIRT1 protein in «young¼ MSCs by 6 and 8,2 times, respectively. The KE peptide reduced gene expression and PARP1 protein synthesis during MSC aging by 2,1 and 5,3 times, respectively; and also reduced gene expression and PARP2 protein synthesis by 2,1 and 4,7 times, respectively. According to molecular modeling data, the KE peptide can interact with the GCGG sequence of double-stranded DNA (dsDNA) in the classical B-form and with the GGGC sequence of the curved dsDNA nucleosome. The indicated dsDNA sequences were found in the promoters of the human SIRT1, PARP1, PARP2 genes. Thus, the KE peptide regulates gene expression and synthesis of SIRT1, PARP1, PARP2 proteins in human mesenchymal stem cells during replicative ageing, which underlies the biological activity and geroprotective effect of this peptide.

Biological Diversity and Remodeling of Cardiolipin in Oxidative Stress and Age-Related Pathologies.

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.

Ants as Object of Gerontological Research.

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.

Protein Poly(ADP-ribosyl)ation System: Changes in Development and Aging as well as due to Restriction of Cell Proliferation.

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.

Coefficient of Variation of Lifespan Across the Tree of Life: Is It a Signature of Programmed Aging?

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.

Is It Possible to Prove the Existence of an Aging Program by Quantitative Analysis of Mortality Dynamics?

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.

Contribution of Quantitative Methods of Estimating Mortality Dynamics to Explaining Mechanisms of Aging.

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.

Thymic Involution in Ontogenesis: Role in Aging Program.

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.

The protein poly(ADP-ribosyl)ation system: its role in genome stability and lifespan determination.

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.