TRANSDISCIPLINARY APPROACH IN FREE RADICAL THEORY OF AGING. CONTRIBUTION OF NIKOLAY M. EMANUEL AND HIS SCIENTIFIC SCHOOL TO GERONTOLOGY

Работа представляет собой обзор научных исследований влияния антиоксидантов-геропротекторов на старение экспериментальных животных и репликативное старение диплоидных клеток человека, выполненных в отделе кинетики химических и биологических процессов «ХИМБИО» Института химической физики АН СССР под руководством академика Николая Марковича Эмануэля в 1960- 1980- е гг. В работах Н.М. Эмануэля и сотрудников было установлено неизвестное ранее явление взаимодействия ингибиторов свободнорадикальных реакций в процессах окисления органических веществ, заключающееся в регенерации более эффективного ингибитора вследствие переноса атома водорода к его радикалу от молекулы менее эффективного ингибитора. Антиоксиданты поливалентны и могут влиять одновременно на многие процессы старения. Данные научной школы Н.М. Эмануэля по увеличению средней продолжительности жизни на 25,3 % и максимальной продолжительности мышей на 55,8 % под действием антиоксидантов, полученные в результате хорошо обоснованных экспериментальных и теоретических исследований, явились весомым аргументом в пользу свободнорадикальной теории старения. The work is aimed to review the results of scientific studies of the effect of antioxidants-geroprotectors on the aging of experimental animals and the replicative aging of human diploid cells, carried out in the Department of Kinetics of Chemical and Biological Processes «KHIMBIO» of the Institute of Chemical Physics of the USSR Academy of Sciences under the leadership of academician Nikolay Markovich Emanuel in the 1960-1980s after pioneer work by D. Harman. By N.M. Emanuel and colleagues, it was established a previously unknown phenomenon of radical interaction of inhibitors in the oxidation of organic substances, which consists in the regeneration of a more effective inhibitor due to the transfer of a hydrogen atom to its free radical from a molecule of a less effective inhibitor. Antioxidants are polyvalent and can simultaneously affect many stages of aging processes. Data from the N.M. Emanuel scientific school on the increase of the average lifespan of mice by 25,3 % and their maximum lifespan by 55,8 % using antioxidants, discovered at the Institute of Chemical Physics of the USSR Academy of Sciences as a result of well-founded experimental and theoretical studies, became a powerful argument in favor of the free radical theory of aging in 1970-ties. This was further promoted by approaches based on the theory of reliability, the damage theory, and as well as an approach based on oxidative activation of the Nrf2 signaling pathway, which maintains the «nucleophilic tone» of protective oxidoreductases.

GEROPROTECTIVE PROPERTIES OF POLYPHENOLIC COMPOUNDS OF FOOD PLANTS

People’s ageing causes economic and social problems all over the world. The article presents the results of the analysis of modern research on ways and means that can eliminate the causes of ageing, prolong the active longevity and working ability of the elderly. It has been established that human health and longevity depend on the specific features of a person’s nutrition and are affected by micronutrient deficiency in the body caused by unbalanced diet. Considering the free radical theory of ageing, which is based on the chemical nature and ubiquity of free radicals, it has been found that consumption of plant foods rich in antioxidants prevents oxidative damage to cellular structures, which is caused by reactive oxygen species. It has been demonstrated that well-known plant antioxidants, such as flavonoids and other polyphenolic compounds, have a protective effect. They modulate energy metabolism in a way conducive to well-being and longevity, and reduce the risk of chronic diseases and ageing. It has been established that the antioxidant effect of flavonoids involves scavenging of free lipoperoxide radicals, inhibition of nitric oxide production, inactivation of peroxynitrite and other oxidants, inhibition of xanthine oxidase and other radical-producing enzymes, chelation of metals. Neuroprotective and radioprotective properties of flavonoids have been revealed. Flavonoids can inhibit regulatory enzymes or transcription factors that are important for the control of inflammatory mediators, affect oxidative stress through DNA interactions, and enhance genomic stability. Combinations of polyphenols can exhibit synergistic or additive beneficial effects. It has been shown that the rational use of plant-based diets rich in polyphenolic compounds helps to reduce the total mortality rate and, in particular, mortality from coronary heart disease, to maintain sustainable weight management, to decrease the frequency and severity of high-risk conditions such as obesity, hyperglycaemia, hypertension, hyperlipidemia, and improve the general condition in cases of long-neglected cardiovascular diseases and diabetes.

Grape seed flour (GSF) extends longevity by improving multi-organ dysfunction and age-associated oxidative stress and inflammation in healthy rat

According to the free radical theory of aging, accumulation of reactive oxygen species (ROS) within mitochondria throughout lifespan leads to impairment of the main biological macromolecules as DNA, lipids and proteins, which might be at the basis of premature aging. One way to test experimentally such a hypothesis consists in intervention studies using antioxidant nutrients aimed at limiting or inhibiting ROS production that should be able to reduce the aging rate and disease pathogenesis. Grape seed flour (GSF) contains high level of phytochemicals among which bioactive polyphenols exhibit numerous biological properties and beneficial health effects as antioxidant, anti-inflammatory, anti-carcinogenic, multi-organ (heart, liver, kidney, and brain among others) protective. The present study aimed at testing the ability of high dosing GSF (4 g/kg bw) used as a nutritional supplement to slow down aging and prolong lifespan of Wistar rats when administered from early life (one month-old animals) till their natural death. Data clearly show that high dose GSF extends organism longevity and healthspan by improving multi-organ damages, systemic fuelling metabolism declines, and alleviated oxidative stress and inflammation in aging rats. Our data support the extending longevity effect of grape polyphenols especially when used as high dosing nutritional supplement or as natural medicine whose appropriate galenic form as solid lipid nanoformulation, is currently under investigation.

Antiradical activity of novel 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol derivatives

The process of studying free radicals began in the middle of the last century (the free radical theory of aging in 1956). Multiple studies have revealed the effect of free radicals on the cells of the body and the development of various diseases, such as diabetes, autoimmune diseases, diseases of the nervous system, and others. As a result, the term antioxidant has emerged, compounds that reduce and prevent the effects of free radicals. Most of the newly synthesized substances are studied for their antiradical properties. 1,2,4-Triazole derivatives are no exception, which has already proven themselves as biologically active compounds. The aim of this work was the investigation antiradical activity among 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol derivatives. Materials and methods. Previously synthesized 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol derivatives were used as test compounds. The research of antiradical activity was based on the interaction between 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol derivatives and 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. DPPH is a stable free radical. The color of its alcoholic solutions were intense purple (λmax = 517 nm). When DPPH interacted with compounds that were capable of scavenging free radicals, it produced products. These products are yellow in color and do not absorb light of the aforementioned wavelength. The study was carried out according to the method. Results. The antiradical activity of 10 new 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol derivatives was studied. Most of the test compounds show antiradical activity against DPPH. Compound 1 was the most active at a concentration of 1 × 10-3 M and the antiradical effect was close to ascorbic acid. Conclusions. The most active compound is 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol, which in a concentration of 1 × 10-3 M has an antiradical effect in 88.89 %. When reducing the concentration to 1 × 10-4 M, also reduces the antiradical activity to 53.78 %. Some conclusions are drawn regarding the “structure – effect” dependence between 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol derivatives: – the introduction of 4-fluorobenzylidene radical (compound 2) into the 4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol molecule results in a slight decrease in activity; – the introduction of 2-hydroxybenzylidene radical (compound 3) into initial molecule results a high antiradical effect, which hardly changes with decreasing concentration; – transformation to 2-((5-(thiophen-2-ylmethyl)-4-((R)amino)-4H-1,2,4-triazol-3-yl)thio)acetic acid has almost no effect on antiradical activity, except for compound 9 (the antiradical effect is reduse).

Biochemical Basis of Altitude Adaptation and Antioxidant System Activity during Autumn Leaf Senescence in Beech Populations

High-altitude tree populations are exposed to severe natural environmental conditions. Among abiotic factors, variable temperatures, early frosts, and high radiation are the factors affecting tree growth at high altitudes. Fagus sylvatica L. exhibits a variety of physiological and genetic traits that allow it to adapt to different forest habitats. This study examines the differences in the biochemical properties of senescing beech leaves between populations originating from different altitudes using a common-garden experiment. Leaves were collected from five-year-old plants from the beginning of August to the end of October for two years. Based on the changes in senescence marker levels the genetic differences and significant correlations between populations’ altitude origin and their biochemical characteristics were identified. According to the free radical theory of leaf senescence, reactive oxygen species (ROS) and senescence markers were highly correlated. In this study, populations from higher altitudes were characterized by earlier and greater increases in ROS content and oxidative stress, which resulted in higher antioxidative system activity. Increases in ROS in high-altitude populations play a controlling role to initiate earlier senescence processes that allow the trees to adapt to harsh climatic conditions. Earlier senescence allows beech trees to maintain a balance between nitrogen metabolism and photosynthetic activity. It allows for remobilization of nitrogen compounds more efficiently and protects the trees from nitrogen loss and prepares them for winter dormancy.

Implication of Dietary Iron-Chelating Bioactive Compounds in Molecular Mechanisms of Oxidative Stress-Induced Cell Ageing

One of the prevailing perceptions regarding the ageing of cells and organisms is the intracellular gradual accumulation of oxidatively damaged macromolecules, leading to the decline of cell and organ function (free radical theory of ageing). This chemically undefined material known as “lipofuscin,” “ceroid,” or “age pigment” is mainly formed through unregulated and nonspecific oxidative modifications of cellular macromolecules that are induced by highly reactive free radicals. A necessary precondition for reactive free radical generation and lipofuscin formation is the intracellular availability of ferrous iron (Fe2+) (“labile iron”), catalyzing the conversion of weak oxidants such as peroxides, to extremely reactive ones like hydroxyl (HO•) or alcoxyl (RO•) radicals. If the oxidized materials remain unrepaired for extended periods of time, they can be further oxidized to generate ultimate over-oxidized products that are unable to be repaired, degraded, or exocytosed by the relevant cellular systems. Additionally, over-oxidized materials might inactivate cellular protection and repair mechanisms, thus allowing for futile cycles of increasingly rapid lipofuscin accumulation. In this review paper, we present evidence that the modulation of the labile iron pool distribution by nutritional or pharmacological means represents a hitherto unappreciated target for hampering lipofuscin accumulation and cellular ageing.

Metabolic Syndrome as the First Stage of Eldership; the Beginning of Real Aging

The history of active worldwide scientific research on mechanisms of aging and the age-associated diseases counts more than five decades. Of these, among the numerous theories of aging, at least 50 years dominated the free radical theory of aging. Since mitochondria were found to be the major producers of free radicals, the research on aging became largely centered on mitochondria. At the end of 80s of the 20th century, physicians have established a new nosological entity named “Metabolic syndrome” comprising several simultaneously existing symptoms and risk factors, which increase with age to 47% in men and 64% for women. The diagnosis of metabolic syndrome (MetS) requires simultaneous presence of at least three out of five medical conditions: visceral obesity, hypertension, high blood sugar, insulin resistance, low serum high-density lipoprotein accompanied with high serum triglycerides. However, from the beginning of the definition of MetS there was, and still is, a rather lovely debate, which of the symptoms must be considered as the main one. In spite of the enormous number of publications on both mechanisms of aging and MetS, there was relatively small progress in understanding the fundamental processes in these closely related problems. On the contrary, the mitochondrial free radical theory was found to be wrong in its current paradigms. In this Chapter we will discuss recent discoveries and hypotheses which open new perspectives in both theoretical and practical approaches to the problems of aging and MetS. We will show how aging and development of MetS are closely related to each other and the normal ontogenesis of human beings. Why men and women have different rates of aging and mechanisms of transition to MetS. We state that MetS is not just a cluster of symptoms, but one of the last steps of individual ontogenesis, namely the first step of eldership when the aging rate may increase manifold.

Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies

Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.