The Scientific Basis for Healthy Aging and Antiaging Processes New York, 2011 Russian_English_book.indd 1 16/12/11 4:25 PM Editors A. ShArmAn and Z. ZhumAdilov Almaz Sharman—MD, PhD, D.M.Sc., Professor of Medicine, Deputy Chairman, Executive Committee, Nazarbayev University; Zhaxybay Zhumadilov—MD, PhD, D.M.Sc. Professor of Medicine, General Director, Center for Life Sciences, Nazarbayev University Russian_English_book.indd 2 16/12/11 4:25 PM The Scientific Basis for Healthy Aging and Antiaging Processes Editors Almaz Sharman and Zhaxybay Zhumadilov New York 2011 liebertpub.com Russian_English_book.indd 3 16/12/11 4:25 PM ISBN: 978-1-934854-xx-x Copyright © 2011 Mary Ann Liebert, Inc. Mary Ann Liebert, Inc. 140 Huguenot Street New Rochelle, NY 10801 All rights reserved. Without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced into a retrieval system, or transmitted, in any form, or by any means (electronic, mechanical, photocopying, recording or otherwise) without the prior written permission of both the copyright owner and Mry Ann Liebert, Inc., the publisher of this work. Published in the United States of America. Russian_English_book.indd 4 16/12/11 4:25 PM Contents List of Abbreviations and Definitions ix Foreword xii Preface xii Chapter I Demographic Transformations, Perspectives on Longevity, and Challenges for Health (A. Sharman) 1 1.1. Demographic Changes in the Twenty-first Century 1 1.2. Increases in Life Expectancy 4 1.3. Longevity and Challenges for Health 6 1.4. Healthy Behavior and the Horizons of Longevity 7 1.5. Low Fertility and an Aging Planet: Good or Bad? 8 References 9 Chapter II Theories of Aging and Its Biology and Physiology (A. Sharman, A. Gulyaev, R. Issayeva, A. Akiljanova) 11 2.1. Free-radical Theory of Aging 13 2.2. Mitochondrial Theory of Aging 14 2.3. Genetic Theory of Aging 15 2.4. Telomeric Theory of Aging 19 2.5. The Inflammatory Hypothesis for Aging 20 2.6. Immune Theory of Aging 20 2.7. Neuroendocrine Theory of aging 21 2.8. The Theory of ”Crosslinking” or Glycosylation of Proteins 21 2.9. Molecular Mechanisms of Aging 22 References 26 Chapter III Biomarkers and Indicators of Aging, Markers of Biological Age, and Predictors of Longevity (T. Nurgozhin, A. Gulyaev) 35 3.1. Integral Biomarkers of Aging 35 3.2. Molecular Biomarkers of Aging 45 3.2.1. Telomeres and Telomerase 45 3.2.2. Indicators of Oxidative Damage 47 3.2.3. Antioxidative Enzymes as Biomarkers of Aging 47 3.2.4. Mitochondrial Microheteroplasmy as a Potential Biomarker of Aging 48 3.2.5. Activity Levels of NADH and FAD as Biomarkers of Aging 49 3.2.6. Heat-shock Proteins. The Level of Expression of HSP-16.2 (The “Stress Gene”) as a Potential Biomarker of Aging 49 v Russian_English_book.indd 5 16/12/11 4:25 PM vi THE SCIENTIFIC BASIS FOR HEALTHY AGING AND ANTIAGING PROCESSES 3.2.7. Apolipoproteins as Biomarkers of Aging 49 3.2.8. Increased Levels of Interleukin-6 as Possible Biomarkers of Aging 50 3.2.9. Decreased Levels of Growth Hormone as Possible Biomarkers of Aging 50 3.2.10. Protein Glycation as a Possible Biomarker of Aging and Age-related Diseases 51 3.2.11. Levels of Gene Expression as Biomarkers of Aging 3.3. Biomarkers Related to Specific Illnesses of Senescence 51 References 52 Chapter IV Geroprotectors (A. Gulyaev, T. Nurgozhin, B. Ermekbayeva) 57 4.1. Effects of Caloric Restriction and Caloric Restriction Mimetics 59 4.2. Sirtuins 60 4.3. Resveratrols and Herbal Polyphenols 63 4.4. mTOR and Rapamycin (Sirolimus) 74 4.5. Biguanides and Metformin 75 4.6. 2-Deoxyglucose 76 4.7. Antioxidants 77 4.8. Mitochondrial Antioxidants 84 4.9. Succinic acid 86 4.10. Neurotropic drugs 87 4.11. Growth Hormone and Other Hormonal Agents 88 4.11.1. Growth Hormone 88 4.11.2. Thyroid Hormones 89 4.11.3. Adrenocortical Hormone 90 4.11.4. Reproductive Hormones and Contraceptives 91 4.12. Melatonin and Epiphyseal Peptides 93 4.13. Immunomodulators 95 4.14. Other Agents and Factors 97 4.14.1. Antiphlogistics 97 4.14.2. Procaine 97 4.14.3. Vitamins 97 4.14.4. Coenzyme Q (Ubiquinone Q10) 98 4.14.5. Inhibitors of Protein Biosynthesis 98 4.14.6. Inhibitors of Crosslinking 99 4.14.7. Enterosorbents 100 4.14.8. Adaptogens 100 4.15. Conclusions About Geroprotective Agents 101 References 103 Russian_English_book.indd 6 16/12/11 4:25 PM CONTENTS vii Chapter V The Gastrointestinal Tract as a Complex Neuroimmunendocrine and Metabolic Organ. The Roles and Applied Aspects of Microbiota of the Gastrointestinal Tract in Gerontogenesis. (Zh. Zhumadilov, A. Kushugulova, A. Gulyaev, A. Supiyev) 123 5.1. Neuroimmunendocrine Components of the Gastrointestinal Tract 123 5.2. Microbiota of the Intestinal Tract: Characteristics in Older Persons 125 5.3. Potential Benefits of Probiotics, and Synbiotics for Older Persons 128 5.4. Mechanisms of Probiotic Effect 136 References 140 Chapter VI Development of Innovative Programs for Healthy Aging: Gerontoengineering and Gerontotechnologies (Zh. Zhumadilov, A. Gulyaev, A. Supiyev, A. Sharman) 149 6.1. Practical view of different types of human aging 149 6.2. Hormesis in Aging and Antiaging 151 6.3. Critical Review of the Basic Theoretical Aspects of Antiaging Technologies 155 6.4. Main Directions of the Most Promising Research 158 6.5. CONCEPT for the Development of Research in the Field of Healthy Aging and Anti-aging up to the Year 2020 161 References 166 Russian_English_book.indd 7 16/12/11 4:25 PM Russian_English_book.indd 8 16/12/11 4:25 PM list of abbreviations and definitions ACE Angiotensin converting enzyme ACS Acute coronary syndrome ACTH Adrenocorticotropic hormone AD Alzheimer’s disease AGT Angiotensinogen AGTR1 Angiotensin II receptor, type 1 AGE Advanced glycation endproducts ALOX Arachidonate lipoxygenase AMPA Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid AMPA-receptors Ionotropic glutamate receptors regulating the permeability of ion chan- nels, sensitive to AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid) action AMPK 5’AMP (adenosine monophosphate)-activated protein kinase, cellular protein kinase controlling energy balance of a cell APOA1 Apolipoprotein A-1 APOB Apolipoprotein B APOE Apolipoprotein E ATCC American Type Culture Collection ARG Regulatory aging gene BAFS Biologically active food supplements BWI Body-weight index CAT Catalase CETP Cholesteryl ester transfer protein CD Clusters of differentiation CR Caloric restriction CR Cardiac rate CREB cAMP response element-binding protein CRP C-reactive protein CS Cholestyrine CYP2D6 Cytochrome P450 2D6 CYP17 Cytochrome P450, family 17 CYP19 Cytochrome P450, family 19 C12TPP Analogue of SkQ lacking plastoquinone CVD Cardiovascular disease DBP Diastolic blood pressure 2DG 2-Deoxyglucose DVS Direct inoculation technology DHEA Dehydroepiandrosterone ix Russian_English_book.indd 9 16/12/11 4:25 PM x THE SCIENTIFIC BASIS FOR HEALTHY AGING AND ANTIAGING PROCESSES DOPA Dihydroxyphenylalanine, physiologically active compound, producing intermediate product in the process of catecholamine synthesis (dopamine, adrenaline and noradrenaline) ECG Electrocardiogram EH Essential hypertension EHEC Enterohemorrhagic Escherichia coli (E. coli)] ESC Embryonic stem cells HER2 Oncogene HLA Human leukocyte antigen HSP Heat-shock protein HGF Hepatocyte growth factor FAD Flavin adenine dinucleotide FOXO Forkhead box class O FSH Follicle-stimulating hormone GABA Gamma-aminobutyric acid GH Growth hormone GHR/BP Growth hormone receptor/binding protein GIT Gastrointestinal tract GnRH Gonadotropin-releasing hormone GSTM1 Glutathione S-transferase Mu 1 GSTT1 Glutathione S-transferase Theta-1 HDL High-density lipoprotein HHD Hypertensive heart disease IBD Inflammatory bowel disease IBS Irritable bowel syndrome ICA Individual chronological age IFNγ Interferon gamma IGF Insulinlike growth factor IGF-1 Insulin-like growth factor-1 IHD Ischemic heart disease IL-1β Interleukin-1β IL-2 Interleukin-2 IL-7 Interleukin-7 IL-6 Interleukin-6 IL-2 Interleukin-2 IL-10 Interleukin-10 iPS-cells Induced pluripotent stem cells IRS Insulin receptor substrates KGF Keratinocyte growth factor LAB Lactic acid bacteria LDL Low-density lipoprotein LE Life expectancy Russian_English_book.indd 10 16/12/11 4:25 PM List of abbreviations and definitions xi LP Lipoprotein LPA Lipoprotein A MAO Monoamine oxidase MCA Middle chronological age of examined persons MI Myocardial infarction MTHFR Methylenetetrahydrofolate reductase MTP Microsomal triglyceride transfer protein mTOR Mammalian target of rapamycin MitQ Mitochondrial antioxidant (10-(6ʹ-ubiquinonyl) decyltriphenylphosphonium) mtDNA mitochondrial DNA NADH Nicotinamide adenine dinucleotide NAT2 N-acetyltransferase 2 NGF Nerve growth factor NIDDM Non-insulin-dependent diabetes mellitus NK Natural killer (referring to a distinct population of lymphocytes) NMDA-receptor (NMDAR; NMDA-receptor) ionotropic glutamate receptor selectively binding N-methyl-D-aspartate PAI1 Plasminogen activator inhibitor type 1 PGC-1 Coactivator PPAR-γ 1 (peroxisome proliferator-activated receptor γ1) PI3K Phosphoinositide 3-kinase PIT1 Pituitary-specific transcription factor PDGF Platelet-derived growth factor PON Paraoxonase PPARa Peroxisome proliferator-activated receptor alpha PPARγ Peroxisome proliferator activated receptor γ PSA Prostate-specific antigen рpm parts per million (units of concentration) RBA CVS Reference biological age of the cardiovascular system REN Renin ROS Reactive oxygen species rRNA Ribosomal ribonucleic acid SBP Systolic blood pressure SCFA Short-chain