Current Aging Science (v.10, #1)

Meet Our Editorial Board Member by Ivan Y. Iourov (1-1).

Introduction by Anthony J. Turner, Natalia N. Nalivaeva, Alexander V. Arutjunyan (4-5).

Aging and Ambiguous ROS. System Genetics Analysis by Vladislav S. Baranov, Elena V. Baranova (6-11).
Famous Free Radical Theory (FRT) of aging, the 50th year anniversary of which is celebrated in 2015 postulates a crucial role of Reactive Oxygen Species (ROS) in aging. Still it is the most robust theory of aging as mitochondria ROS production (mtROSp) correlates well with four principal ''rules” of aging being universal, endogenous, progressive, and deleterious. Vast number of experiments in different species prove mutagenic effect of ROS and their carcinogenic properties. So far, FRT stimulates the search of new pharmaceuticals with antioxidant activity. However, some recent experimental data and clinical findings render doubt to ROS as a principal senescence drivers and come in conflict with original version of FRT. Growth stimulating effects of ROS and their modest antitumor properties support these objections. One should remember that FRT is only one of the numerous theories of aging. Molecular mechanisms of senescence involve all living systems and numerous metabolic pathways which are also variable owing to the unique properties of individual genome and unique epigenetic modulations operating throughout the lifetime thus making aging a unique private matter. Universal theory of aging that incorporates and explains all known and suggested mechanisms of aging, is illusive. However, knowledge of unique peculiarities of individual genome, its feasible editing and efficient epigenetic regulation of metabolic pathways give a chance to postpone aging and extend period of active longevity.

There are two generally known concepts in biology of aging. Accordingly to the first one, there is a program of aging. The alternative concept advocates that aging proceeds stochastically. In this area of research, free radical-theory of aging, which was put forward by Denham Harman in fifties of XXth century, has determined the most heuristic line. The goal of this review is to demonstrate how the aging program and the aging stochastics are united on the basis of the systems theory of reliability. On this basis, universal features of aging, such as the exponential growth of mortality rate with time and correlation of longevity with the species-specific resting metabolism, are naturally explained. The stochastic malfunctions of the mitochondrial electron transport nanoreactors, which produce the oxygen anion-radicals (O2•— ) as by-products of respiration, seem to be of first importance. As a reducing agent, O2•— affects the ratio of NAD(P)H/NAD(P)+ and, by changing the activity of sirtuins, slows down renewal of biomolecular constructs. As a consequence, the oxidative-stress products and other metabolic slag accumulate with the resulting impetus to autophagic or apoptotic cell death accompanied with age-associated clinical disorders. Based on this reliability-theory approach, one can estimate that the longevity of human brain could reach 250 years should the antioxidant defense against the free-radical failures be perfect. Thus, the free-radical redox timer serves as effective stochastic mechanism of realization of the programmed deficiency in reliability of biomolecular constructs.

We have provided an overview, based on the literature and our data. In accordance with the theory of D. Harman free radical processes cause damages that can accumulate and contribute to aging of the organism. Atherosclerosis and diabetes are developing for a long time so they are manifested predominantly in old age. We found an increase in the level of free radical peroxidation products and decrease in the activity of antioxidant enzymes in the tissues of animals with experimental atherosclerosis. Similar changes were found in the blood of patients with atherosclerosis and aortic autopsy material with atherosclerotic lesions. Thus, it was revealed that oxidative stress occured under atherosclerosis, and the arteriosclerosis to "Free Radical Pathologies" was attributed. Later it was discovered by different authors that oxidized Low Density Lipoproteins (LDL) and malonyldialdehyde- modified LDL accumulated during atherogenesis, causing damages of vascular wall. Under diabetic hyperglycemia glucose co-oxidized during free radical lipoperoxidation. This process promoted the transformation of oxidative stress to carbonyl stress with accumulation of biologically active dicarbonyls, including glyoxal and methylglyoxal. We show that the glyoxal-modified LDL were captured by cultured macrophages with a higher efficiency than the MDA-modified LDL. This could facilitate the more rapid development of lipoidosis in the vessel wall (due to the formation of foam cells) and manifestation of atherosclerosis under diabetes. We found that in patients with diabetes there was a sharp decrease in the activity of antioxidant enzymes as a result of the modification of the active center under development of carbonyl stress. We expressed a hypothesis about a common molecular mechanism of vascular wall damages under atherosclerosis and diabetes.

Role of Reactive Oxygen Species in Premature Ageing of the Female Reproductive Function by Andrew Korenevsky, Yulia Milyutina, Ljudmila Kozina, Gleb Kerkeshko, Alexander Arutjunyan (26-31).
Industrial xenobitics, as well as endogenous damaging factors, such as L-homocysteine, are a well-known source of reactive oxygen species that disrupt biological processes. Among many others, luteinizing hormone releasing hormone synthesis and secretion mediated by a variety of neurotransmitters, which are under control of the hypothalamus and pineal gland, may be put in peril by reactive oxygen species. Their formation can be one of the reasons for the reproductive function shutdown in ageing as the generic response to the damaging factors independent of their nature. We review recent findings demonstrating the role of reactive oxygen species in disrupting the circadian signal originated in the main pacemaker of the organism, the suprachiasmatic nuclei of the hypothalamus, on its way to the hypothalamic areas responsible for the luteinizing hormone preovulatory surge.

The accumulation of cerebral amyloid β-peptide (Aβ) is a key precipitating factor for neuronal cell death in Alzheimer's Disease (AD). However, brain Aβ levels are modifiable since there is a balance between its formation from the Amyloid Precursor Protein (APP) and its removal by clearance mechanisms, which can be either through proteolysis or by protein binding and subsequent transport). Among the major enzymes degrading brain Aβ are several zinc-proteases: neprilysin (NEP), its homologues NEP2 and the Endothelin Converting Enzymes (ECE-1 and -2) and also the Insulin-Degrading Enzyme (IDE). During the ageing process, and under certain pathological conditions (e.g. ischemia and stroke), the expression and activity of these enzymes decline, which leads to a deficit of Aβ clearance and its accumulation in the brain. Some of these changes in the enzyme properties are due to their reduced expression and/or structural modification by reactive oxygen species. In this review paper we shall discuss some mechanisms of regulation of Amyloid-Degrading Enzymes (ADEs) and possible therapeutic approaches which might prevent their decline with age and after pathology.

Cellular and Molecular Mechanisms of Action of Mitochondria-Targeted Antioxidants by Boris A. Feniouk, Vladimir P. Skulachev (41-48).
Reactive oxygen species generated in mitochondria are an important factor contributing to mitochondrial and cellular dysfunction underlying many degenerative diseases, chronic pathologies and aging. The idea of delivering antioxidant molecules to mitochondria in vivo to treat these diseases and slow aging intensively developed in the last 20 years. Derivatives of quinones covalently conjugated to a lipophilic cation (e.g., MitoQ and SkQ) were the most extensively studied mitochondria-targeted antioxidants. These compounds have now been used in a wide range of in vitro and in vivo studies, as well as in clinical trials in humans. Here, we review recent progress in this field with a special attention on molecular mechanisms of rechargeable mitochondria-targeted antioxidants.

A simple hypothesis that aging results from gradual accumulation of occasional damage inflicted by ROS to DNA, proteins and lipids is apparently insufficient. More and more pieces of evidence indicate that the damage in question is programmed. Moreover, the imbalance in ROS-dependent regulatory mechanisms and compromised ROS signaling are underlying many pathologies and aging. Chain reactions of cardiolipin peroxidation initiated by mitochondrial ROS seem to play a key role in these degenerative processes. Such reactions are specifically abolished by mitochondriatargeted antioxidants.

Physiological and Biochemical Mechanisms of Lifespan Regulation in Rats Kept Under Various Light Conditions by Evgeniy A. Khizhkin, Victor A. Ilukha, Irina A. Vinogradova, Lyudmila B. Uzenbaeva, Tatiana N. Ilyina, Victoria D. Yunash, Artem V. Morozov, Vladimir N. Anisimov (49-55).
Background: The present study was aimed to identify how age-related changes in some physiological and biochemical systems are related to changes in the life span of rats with long-term pineal gland hypo- and hyperfunction induced by constant light and constant darkness, respectively.

Methods: At the age of 25 days the rats were randomly divided into 3 groups: standard light/dark regimen (LD), constant light (LL) and constant darkness (DD). Age-related Antioxidant System (AOS) changes in liver tissues, alteration of immunoreactivity in blood smears were investigated, pubescence and lifespan of the animals were determined.

Results: Modification of the level of melatonin synthesis induced by constant light results in interrelated rearrangements in the functioning of the investigated physiological systems. Elevated activity of the antioxidant system extends the lifespan, while at the same time slowing down pubescence and altering the morpho-functional properties of leukocytes in blood.

Conclusion: The absence of light/dark alternation (constant light and constant darkness) affects only those physiological indices that follow the organism's circadian rhythms (Activity of Antioxidant Enzymes (AOE), levels of individual immune system cell types), whereas changes in the parameters not governed by circadian fluctuations (vitamin concentrations, pubescence, and aging) depend on the level of melatonin produced by the pineal gland.

Fullerenes as Anti-Aging Antioxidants by Yuliana P. Galvan, Igor Alperovich, Petr Zolotukhin, Evgenia Prazdnova, Maria Mazanko, Anna Belanova, Vladimir Chistyakov (56-67).
Here we review fullerenes biological effects focusing on their antioxidant and anti-ageing action. A scope of various poisonous and healing properties reported in literature for fullerene and its derivatives is analyzed. The review begins with the history of fullerenes discovery and their main properties. Then we focus on the longevity and antioxidant action, including the confrontation of available experimental data and theoretical modeling of buckminsterfullerene C60. Special attention is given to our hypothesis concerning the possibility of fullerenes to act as mitochondria protonophore and various simulations of the transport of C60 and its hydroxylated and other derivatives through lipid bilayer membranes, which can account for scavenging capacity of fullerenes for reactive oxygen species and their acting as mild mitochondrial respiration uncouplers. Extension of the theoretical modeling to the mitochondria membranes and implications on the real biological systems is analyzed. Finally, we focus on the toxicity evaluation and current therapeutic usage of fullerenes. The review contains a comprehensive discussion of both papers published by 2016 and our own research results.

Chemical Modification of Ginsenoside on Cell Viability and Cytokine Secretion by Brandi S. Betts-Obregon, Magaly Salinas, Dale Oladunni, George R. Negrete, Andrew T. Tsin (68-75).
Background: Rb1 is a ginsenoside steroid glycoside found exclusively in the plant Panax ginseng. In an earlier report, we showed that Rb1 increased cell proliferation and reduced VEGF (vascular endothelial growth factor) secretion by human retinal pigment epithelial (ARPE19) cells.

Objective: In the present study, we hypothesized that chemical modification of Rb1 changes the level of VEGF secretion by ARPE19 cells.

Method:Three derivatives of Rb1 were chemically synthesized by hydrogenation (Rb1-H2), acetylation (Rb1-Acyl), and epoxidation (Rb1-Epoxy). Structural modifications were confirmed by 1H Nuclear Magnetic Resonance (NMR) spectra and Mass Spectrometry (MS). To test the biological activity, chemically modified compounds were added to cell culture media and incubated for 72 hours at a concentration of 250 nM at 37°C. Conditioned media were collected and cells were harvested/ counted after treatment. Viable cell numbers were determined by the trypan blue dye exclusion method and VEGF levels by Enzyme-Linked Immunosorbent Assays (ELISA).

Results: Consistent with the prior report, results of the present study show Rb1 increased cell proliferation and decreased VEGF secretion. Similar to Rb1's effect on cell proliferation, treatment with Rb1-H2, Rb1-Acyl and Rb1-Epoxy resulted in an increase in cell numbers. In contrast to Rb1- induced decrease in VEGF secretion, treatment with Rb1-H2, Rb-Acyl and Rb1-Epoxy resulted in increased VEGF levels.

Conclusion: Chemical modifications of the ginsenoside Rb1 significantly affect the biological activity of VEGF secretion by ARPE19 cells. Additional SAR (Structure Activity Relationship) experiments will be conducted to study the detailed mechanisms by which how specific modifications of Rb1 functional groups alter biological activities.

The Past is Never Dead; It's Not Even Past by Stephen C. Bondy (77-77).