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

Biochemistry (Moscow) - This review discusses genetic and molecular pathways that link circadian timing with metabolism, resulting in the emergence of positive and negative regulatory feedback...     

Allergen-Specific Immunotherapy with Monomeric Allergoid in a Mouse Model of Atopic Dermatitis

Atopic dermatitis (AD) is a widespread and difficult to treat allergic skin disease and is a tough challenge for healthcare. In this study, we investigated whether allergen-specific immunotherapy (ASIT) with a monomeric allergoid obtained by succinylation of ovalbumin (sOVA) is effective in a mouse model of atopic dermatitis. An experimental model of AD was reproduced by epicutaneous sensitization with ovalbumin (OVA). ASIT was performed with subcutaneous (SC) administration of increasing doses of OVA or sOVA. The levels of anti-OVA antibodies, as well as cytokines, were detected by ELISA. Skin samples from patch areas were taken for histologic examination. ASIT with either OVA or sOVA resulted in a reduction of both the anti-OVA IgE level and the IgG1/IgG2a ratio. Moreover, ASIT with sOVA increased the IFN-γ level in supernatants after splenocyte stimulation with OVA. Histologic analysis of skin samples from the sites of allergen application showed that ASIT improved the histologic picture by decreasing allergic inflammation in comparison with untreated mice. These data suggest that ASIT with a succinylated allergen represents promising approach for the treatment of AD.     

Evolution of the Permian family Spirolegoceratidae (Goniatitida,Ammonoidea)

The evolution of the Permian ammonoid family Spirolegoceratidae is discussed and a new phylogenetic reconstruction is proposed based on new data. Two subfamilies are recognized within the family Spirolegoceratidae: Spirolegoceratinae Nassichuk and Sverdrupitinae subfam. nov. A new genus, Archboldiceras, is proposed to accommodate the Australian species Uraloceras lobulatum and U. whitehousei. Species of the genus Sverdrupites Nassichuk, 1970 are described based on new material from the Volga-Urals Region. The new species S. bogoslovskayae from the Gerkinskaya Formation of Novaya Zemlya previously identified by M.F. Bogoslovskaya as S. amundseni is described.     

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.     

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 (CV_LS). It is believed that a relatively small (～20%) value of CV_LS 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 CV_LS, 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 CV_LS 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 CV_LS 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.     

Testing of geroprotectors in experiments on cell cultures: Choosing the correct model system

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).     

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.     

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.