[Polyphenols of natural origin against age-related disorders of tissue homeostasis.]

Aging-related disorders of tissue homeostasis may lead to excessive cell proliferation in the form of cancer and to extracellular matrix expansion in the form of fibroses. Death rates attributed to both of the conditions are decreased, according to epidemiological evidence, upon increased dietary intakes of polyphenols, including flavonoids, stilbenes, lignans, and curcuminoids. That is, polyphenols, although they have very different structures, unidirectionally influence the two opposite sides of balance in tissue homeostasis: the cells, which are able, and the extracellular matrix, which is unable to proliferate. The common features of fibroses and cancer are the transformation of fibroblasts into myofibroblasts (MF) and the epithelial- and endothelial-to-mesenchymal transitions (EMT and EndMT), which shift cell proportions in tissues toward MF. The increased ability of MF to produce collagen promotes fibroses in non-cancerous tissues, and EMT and EndMT enhance cancer progression. These processes are influenced by not polyphenols themselves due to their interactions with different sterically suitable targets, but by polyphenol oxidation products, which are all highly electrophilic. By binding to the SH-groups of the KEAP1 protein complexed with the NRF2 protein, they release NRF2, which is generally known as a transcription factor involved in activating the genes implicated in cell antioxidant defenses. In the present review, attention is drawn to the published data about NRF2 ability to attenuate TGFß1 signaling, which promotes fibroblasts conversion into MF and enhances EMP and EndMP, that is increases the phenotypic instability of cells. Thus, the anticarcinogenic and antifibrotic effects of polyphenols may both involve cell phenotype stabilization, which may contribute to the geroprotector effects of polyphenols.

The Effect of Inactivating Heterozygous Mutation in NBS1 Gene on DNA Damage and Repair Markers and Apoptosis Markers in Mice.

We studied the state of the DNA repair system and apoptosis in young mice carrying heterozygous inactivating mutation in the NBS1 gene (c.1971insT, p.Arg658Stop). In the peripheral blood cells of 4-month-old NBS1insT males, the %DNA in the comet tail was higher by 10% than in wild-type mice (wt) (p<0.05). In hepatocytes of NBS1insT mice, the proportion of γH2AX+ nuclear regions marking DNA double-strand breaks was lower by 2 times than in wt mice (p<0.05), which can be an indicator of less efficient DNA repair. In the kidney tissue of NBS1insT mice, a tendency towards the proapoptotic ratio of Bax and Bcl-2 protein markers was revealed against the background of their reduced expression. Thus, the disturbances detected NBS1insT mice in young age suggest that this model is promising for further studies of carcinogenesis.

[The lifespans of scholars referred to different disciplines according to data from diverse sources: Inferences and challenges.]

Human lifespan is known to correlate positively with education level. In the present paper, it is explored whether there are significant differences in lifespan among those whose education may be reasonably rated as the highest possible, i.e. among scholars referred to different scientific disciplines. The publications where the lifespans of scholars were estimated against the general population are reviewed, and the estimates are compared with those derived from the Database of Persons Included in Encyclopedias (DBPE), which has been being developed by the authors since 2008 based on Wikipedia records. With all caveats associated with the peculiarities of the procedures of including biographic data in Wikipedia, the estimates derived from the latest version of DBPE correspond to earlier estimates and confirm the conclusions based on other data sources: scholars' mean age at death (MAD) and life expectancy (LE) steadily increased since the Medieval period up to the modern time, were higher than those of the general population, and where the highest among the scientific elite. An unexpected finding was that MAD and LE of economists were usually the highest, whereas those of the mathematicians were lowest compared with specialists in other research fields. The difference between the two extreme cases ranges from ca. 3 to 5 years in different historical periods. Further examination of the difference between the extremes may reveal what factors behind it may be at work generally, even though they manifest themselves less overtly in other cases.

[Theory and practice of aging upon COVID-19 pandemic.]

Never before in history, aging was such a significant factor for epidemics as it is now for the current COVID-19 pandemic, which features a drastic shift of mortality towards older ages. Our analysis of data on COVID-19-related mortality in Spain, Italy, and Sweden has shown that, in the range of 30 to 90 years of age, each dependency of the logarithm of mortality upon age is linear, and all regression lines are strictly parallel to those related to the total mortality in accordance with the Gompertz law. In all cases, irrespective of the stage and place of epidemic, mortality doubling time in this age range is close to 7,5 years. The rates of being infected with the SARS-CoV-2 coronavirus and of being diagnosed due to the symptomatic manifestations of the infection are dependent on age to a far lesser degree. With account for these observations, three messages are put forth: 1) Older persons are the principal victims of both SARS-CoV-2 and measures undertaken to control its spread; 2) Older persons are not the principal driving force of SARS-CoV-2 spread; 3) Older persons can and should be engaged in combating the pandemic and its consequences; however, not via selective social distancing and other discriminative measures. People aged over 65 years constitute a significant part of the current population. They have specific interests and needs, which deserve no less respect than those of any other age group. This includes the right for the quality of life that remains sustained under the emergency conditions. Since the prospects for controlling the SARS-CoV-2 are dubious, those in charge of decisions concerning «people aged above 65¼ should mind that currently, unlike in the medieval ages, 65+ is the individual future of almost everyone.

[Comparative analysis of experimental data about the effects of various polyphenols on lifespan and aging.]

To analyze experimental data on the effect of various polyphenolic compounds on lifespan of mice, we approximated survival curves with the Gompertz model in its minimal form, which does not account for the heterogeneity of samples and the age-independent mortality. The plots of regressions of log0 (logarithm of the initial mortality) on  (the rate of aging) in series of control samples were used to assess the deviations of vectors directed from control to experimental data from the slopes of the control regressions. The analysis of published data suggests that resveratrol, polyphenol-containing grape skin extract, metformin, tocopherol, and the antioxidant SkQ1 do not produce changes beyond those possible upon comparing of different samples of a control population. The effect of the polyphenolic composition BP-C3 on female SHR mice is unique in being associated with a significant decrease in the rate of aging. The effect may be partly contributed to by the antioxidant properties of BP-C3. Its antioxidant capacity determined in vitro is comparable with that of established antioxidants, such as dihydroquercetin. Its effects in vivo include the ability to ameliorate reduction in the peroxide-decomposing activity of RBC lysates from male BALB/c mice treated with 5-fluorouracil.

[Gender-specific effects of neonatal administration of melatonin on lifespan and age-associated patholgy in 129/Sv mice.]

Melatonin was administered at the dose of 1,2 mcg per capita (an equivalent to pediatric dosages) at days 1, 3 and 5 postpartum to 129/Sv mice, which were followed thereafter till their natural deaths. In adult males, findings included a decrease in body weight and an increase in the contribution of pulmonary lesions, which were revealed upon postmortem examinations, to the overall mortality. In adult females, no changes in body weight occurred, the proportion of middle- and late-age mice having irregular estrous cycles increased, and mortality associated with uterine hemangiomas was accelerated. Trends in malignant tumor yields were different: a decrease in males and an increase in females. Tends in survival patterns were expressed as significant increases or decreases in the lifespans of the last 25% and 10% of male or female survivors respectively. An analysis of the complete survivorships curves in terms of the Gompertz model showed that changes in the initial mortality and aging rate were within the limits determined by the artifactual component of the Strehler-Mildvan correlation between these parameters. On a whole, the trends found in the present work were opposite in males and females being mostly favorable for the former and adverse for the latter. Gender specificity should be kept in mind upon considering the use of melatonin by children and their mothers.

[Where does the Preston curve lead us?]

World Bank and Russian Federal State Statistics Service data were used to analyze cross-country correlations between life expectancy (LE) and per capita gross domestic product (pcGDP). The resulting world trend (Preston curve) as of 2015 was compared with the trend revealed by plotting regional LE vs. pcGDP related to the major administrative areas of the Russian Federation (RF). Besides that, correlations between the same parameters related to different years, from 1960 to 2015, were examined in each of several selected countries representing the upper and lower extremes of pcGDP and LE. The same has been done with per capita health care expenditures (pcHCE) vs. LE. In all cases, the points related to RF are found significantly lower the respective regression lines (Preston curves) built based on all points. The LE vs. pcGDP and LE vs. pcHCE plots and their extrapolations built based on data related to different years in the same country run markedly lower in the case of RF compared with other countries, including Tajikistan and the Republic of Congo. At the same time, the proportion between pcGDP and pcHCE has been shown to be the same throughout all years and all countries. Taken together, these observations suggest that the effectiveness of investing the available resources into LE, that is in human life quality, is markedly lower in Russia compared not only with Finland and Japan, where pcGDP and pcHCE are several times greater than in RF, but also with Congo and Tajikistan, where these parameters are several fold smaller, than in RF. This means that by merely increasing pcGDP and pcHCE it is impossible to increase LE in Russia above 80 years declared a national priority. Identifying the factors responsible for the above disproportions is beyond the scope of the present paper. However, the mere awareness of their existence is essential as an incentive to take special efforts aimed at the identification and neutralization of these factors.

[Why and how do we age? - a single answer to the two questions.]

The chemical properties of compounds involved in metabolic processes, even the core ones, such as glycolysis and Krebs cycle, are not limited to what is realized via enzymatic reactions, because the properties include the abilities to form spontaneousely covalent bonds with other compounds, incuding those incorporated in macromolecules. The effects of the gene that codes for an enzyme, which catalizes the formation of a metabolite, which features such extra properties, may be regarded as antagonistically pleiotropic. The effects that are realized via the product of the reaction catalysed by the enzyme coded by a gene are required for current viability. The effects that are mediated by the spontaneous formation of covalent bonds between the same product and slowly renewable macromolecules will be increasingly deleterious with increasing time of their accumulation provided by the positive effects. Thus, the antagonistically pleiotripic effects are not late-acting, as it is commonly believed, but rather they are cumulative. Since these effects are inseparable from metabolism, they may be labeled "parametabolic". The driving force produced by these effects is sufficient for aging to take place in any system that exists due to metabolic processes therein and proliferate due to information stored by components featuring much slower turnover compared with that of metabolites. Thus, we age because of the chemical properties of our constituents and do it so as it is determined by these properies realized within conditions of our bodies. Aging is neither a direct product of evolution (such as a program that determines the span of life), nor a byproduct (a delayed payment for current advantages). Aging results from limitations that the immanent physicochemical properties of metabolites impose on the capabilities and outcomes of evolution by natural selection, and this is what distinguishes aging from the tear and wear of inanimate objects.

[Biochemical and genetic aspects of pathogenesis of schizophrenia].

Some molecular-biological and genetic concepts of development of schizophrenia are discussed. The main attention is paid to the ontogenetic aspect of dopaminergic disturbances and to role of risk factors, including stress, responsible for interaction between the nervous, endocrine, and immune systems during development of schizophrenia.

[The issue of feasibility of a general theory of aging. II. The parametabolic theory of aging].

Life on Earth has evolved from the chemical world, so nothing of chemistry has disappeared in biology even though of might become unapparent being obscured or counteracted by some other chemistry according to the biological design. Living bodies incorporate molecules involved in biological functions with all their potencies, not only those implicated in the respective functions. The useful properties are exploited by enzymatic catalysis. The excessive properties have manifestations that accompany the enzymatic processes and may be not only irrelevant but even overtly adverse. The accumulation of damage caused by these multiple parametabolic processes results in the reduction of vitality generally known as aging. Another chemical legacy is the exponential dependency of mortality rate on age, which emerged because, in the multimolecular prebiotic aggregates, the role of the main variable in the Arrhenius equation for their decomposition shifted from temperature to activation barrier, which was compromised by the parametabolic processes. This resulted in the shift of the effect of the ever-acting parametabolic damage, as it is manifested in changes in mortality, to later ages. Numerical modelling shows that, in this case, the evolutionary acquisition of new functions that increase resistance to the causes of death may be associated with increased rate of functional decline and reduced cohort lifespan yet increased investment of resources into progeny and thus increased overall fitness, favoured by natural selection.

[The issue of feasibility of a general theory of aging I. Generalized Gompertz-Makeham Law].

Aging and longevity are interrelated so intimately that they should be treated with a unified theory. The longevity of every single cohort of living beings is determined by the rate of their dying-out. In most cases, mortality rates increase in accelerated fashions to reach values making the bulk of each finite cohort completely exhausted within a relatively narrow time interval shifted to the end of its resulting lifespan. Among simple functions with biologically interpretable parameters, the best fit to this pattern is demonstrated by the Gompertz-Makeham Law (GML): mu = C + lambda x e(gamma x t). A generalized form of GML mu = C(t) + lambda x e(-E(t)) is suggested and interpreted as a law of the dependency of mortality upon vitality rather than on age. It is reduced to the conventional GML when E depends linearly on t, that the age is an observable correlate of unobservable vitality. C(t) captures the inherently irresistible causes of death. The generalized GML can accommodate any mode of age-dependent functional decline, which should be placed into the exponent index to be translated into changes in mortality rate, and is compatible with any sort of cohort heterogeneity, which may be captured by substituting of GML parameters with relevant distributions or by combining of several generalized GML models. The generalized GML is suggested to result from the origin of life from the chemical world, which was associated with the transition of the role of the main variable in the Arrhenius equation k = A x exp[-Ea/(R x T)] for the dependency of chemical disintegration on temperature from T to Ea upon the transition from molecular to multimolecular prebiotic entities. Thus, the generalized GML is not a result of biological evolution but is a sort of chemical legacy of biology, which makes an important condition for life to evolve.

[The issue of feasibility of a general theory of aging. III. The theory and practice of aging].

An analysis of demographic data about human mortality and lifespan carried out according to the complete Gompertz-Makeham model mu = C+ lambda x e(gamma x t) shows that, over the last 100 years, lifespan expectation increased almost exclusively because the Makeham parameter C decreased. The often reported apparent changes in the demographic aging rate gamma and in the initial vitality, which is proportional to -Inlambda, are likely to be largely an artifact of the attempts to decompose mortality data that are related to conditions that significantly change within the time scale comparable with human lifespan, whereas the correct decomposition is possible only for strictly homogenous populations under strictly stationary conditions. The comparison of this situation with animal experiments suggesting possible interferences that may decrease aging rate and/or increase lifespan reveals that the main factors of reduced mortality and increased lifespan in humans are limited to one's personal commitment to follow longstanding traditional recommendation for healthy life, which may help to bring one's lifespan about 10 ten years closer to the reliably recorded maximum of 122 years. The bottleneck for the realization of this reserve resides not in science but rather in public and individual mentality.

[Numerical modeling of ideal cohorts of aging organisms obeying the Gompertz-Makeham law in association with the Strehler-Mildwan correlation]. / Chislennoe modelirovanie ideal'nykh kogort stareiushchikh organizmov pri sobliudenii zakona Gomperttsa-Meikkhema i korreliatsii Strelera-Mildvana.

The Gompertz-Makeham law (-dn/dt x l/n(t)=C+lambdae(gammat)) so as other genuine laws of Nature is strictly applicable only to ideal objects (populations and cohorts) analogously to laws of mechanics or thermodynamics, which are exactly true only for such physical abstractions as mass points or ideal gases. Therefore, a biologically meaningful interpretation of the parameters of this law is likely to be more important for understanding the aging process than devising of alternative analytical descriptions of biodemographic processes for the sake of a better fit only. Numerical modeling of ideal cohorts of aging organisms obeying the Gompertz-Makeha law makes it possible to differentiate possible real and apparent changes in mortality patterns that occur in human history and in evolution and are observed in gerontological experiments and to demonstratively show such effects as the dependency of longevity upon population size, the evolutionarily important possibility of reciprocal changes in the mean and maximal longevity, or detection of apparent changes in negatively correlated aging rate and vitality when the Makeham term is ignored, which is usual in demography. The basic difference between the Makeham term Cand Gompertz term lambdae(gammat) is suggested to be not that the former is constant, whereas the latter is age-dependent, but that the former comprises the contributions of inherently irresistible stresses to mortality, whereas the latter comprises the contributions of resistible stresses to mortality and shows how changes in the ability to resist them is translated into changes in mortality.

[Understanding aging]. / Ponimanie stareniia.

The essay reviews specific features of medical, biological, and biotechnological approaches to studying and understanding of biological phenomena exemplified with aging.

[Biochemistry of lifespan extension]. / Biokhimiia prodleniia zhizni.

A review of biochemical mechanisms underlying the known approaches to extension of lifespan and/or slowing down of ageing suggests that they all modify balances between generation of active oxygen and carbonyl species and the mechanisms that protect from their damaging effects or repair their consequences. A likely common target of the geroprotector effects of antioxidants, melatonin, and antidiabetic biguanides is the mitochondrial respiratory chain. In biological species that evolved through r-selection (nematodes, fruit flies, mice, and rats), the balance between anabolic/reproductive and self-maintenance/protective functions is the most significant modifiable factor of longevity and ageing. At the molecular level, the pivot of this balance is formed by the forkhead-type transfactors, whereas at the physiological level the balance is determined by dietary calories and physical activity via mechanism in which the central role is played by insuline-like peptides and, also, growth hormone and leptin or their functional analogs. In biological species that evolved through K-selection (higher primates, particularly humans), the latter balance is less important, and the biochemical factors of aging are more refracted through the higher regulatory systems, of which the most significant are catecholaminergic mechanisms of regulation of neuroendocrine-immune interrelationships and the circulatory system. This results in a decreased geroprotector potential of calory restriction and in an increased importance of the optimal physical activity. When these conclusions are compared with demographic data, it comes out that virtually all advances in gerontology may be reduced to maxims of healthy ageing known from extreme antiquity. Under optimal socioeconomic conditions, the chances to approach the documented world record of human longevity (122 years) may be increased by (not to mention getting rid of smoking and other abuses) high physical activity, adequate nutrition enriched in fresh fruits, optimism, and timely treatment of specific diseases. The most important bottleneck in the realization of these reserves is currently the public consciousness rather than the science.

[Aging of the pineal gland]. / Starenie épifiza.

The age-related changes in the pineal gland are functional rather than organic, which makes their correction or prevention more tenable. The amelioration or inhibition of some age-related impairments of the pineal gland were observed with dietary restriction and the use of S-adenosylmethionine or MAO-A inhibitors. A threefold increase in nocturnal melatonin peaks occurs in old rhesus monkeys treated with a synthetic peptide Ala-Glu-Asp-Gly (Epithalon) designed basing on the amino acid content of a pineal peptide extract Epithalamin. Other effects of Epithalon markedly overlap with melatonin effects. Besides life extension in mice and fruit flies, Epithalon effects include the postponing vision loss in Campbell rats with hereditary pigmental dystrophy. A uniting aspect of such a range of activities might be the participation of transcription factors, since they are often highly conservative in evolution and, on the other hand, may be strictly tissue-specific. The targets of Epithalon may include transfactors that in mammals are specific for the pineal gland and retina and exhibit impaired functions in the aged pineal gland.

[The natural history of telomeres]. / Estestvennaia teoriia telomer.

Telomeres are end chromosome structures, which may shorten because of DNA end replication problem and non-reparability of free-radical damage to telomeric DNA. Telomerase is an enzyme serving to maintain telomere length at a species-specific level. The absence of telomerase in somatic cells is widely believed to be the cause of the limited proliferative potential of somatic cells achieved when telomere length, which diminishes over successive cell generations, becomes critically short. However, telomeres are known to be highly heterogenous with regard to their length even in cloned cell populations. In this review data on telomer length distribution and changes in characteristics of these distributions observed over time are considered along with hypotheses about the nature of these phenomena. The following conclusions are drawn: causes of the known features of telomere length distribution are not limited to mere scattering and measurement error, and so any concepts concerning the relationships between telomere length and cell fate should take characteristics of telomere heterogeneity in consideration; the ratio of the initial telomere length and the rate of telomere shortening does not determine the proliferative potential of non-transformed cell populations and does not limit the lifespans of multicellular organisms; telomerase functions in non-germinal cells are either unnecessary or unknown; telomere heterogeneity may result from the stochastic nature of events committing cells to terminal differentiation and/or the loss of cell capacity to proliferate.