Stenalderkost. Umahro Cadogan
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1 Stenalderkost Umahro Cadogan 1
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8 2176 Current Pharmaceutical Design, 2007, 13, Homo obesus: A Metabotrophin-Deficient Species. Pharmacology and Nutrition Insight G.N. Chaldakov 1,3,*, M. Fiore 2, A.B. Tonchev 1,3, D. Dimitrov 3, R. Pancheva 3, G. Rancic 4 and L. Aloe 2 1 Division of Cell Biology, Medical University, Varna, Bulgaria, 2 Institute of Neurobiology, National Research Council-European Brain Research Institute, NGF Section, Rome, Italy, 3 Nutrigenomics Center, Medical University, Varna, Bulgaria and 4 Department of Histology and Embriology, Medical Faculty, Nis, Serbia Abstract: In most countries the prevalence of obesity now exceeds 15%, the figure used by the World Health Organization to define the critical threshold for intervention in nutritional epidemics. Here we describe Homo obesus (man the obese) as a recent phenotypic expression of Homo sapiens. Specifically, we classified Homo obesus as a species deficient of metabotrophic factors (metabotrophins), including endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing. Here we propose that pharmaceuticals, nutraceuticals and xenohormetics targeting transcriptional, secretory and/or signaling pathways of metabotrophins, particularly adiponectin, nerve growth factor, brain-derived neurotrophic factor, interleukin-10, and sirtuins, might be new tools for therapy of Homo obesus. Brief comment is also given to (i) exogenous metabotrophic agents represented by various classes of drugs, and (ii) adiponutrigenomics of lifspan. Key words: Metabotrophins, metabotrophin-targeted pharmacology. When someone declared that life is an evil, Diogenes said: Not life itself, but living ill. INTRODUCTION Obesity is one of the greatest public health challenges of the 21st century. Obesity is already responsible for 2-8% of health costs and 10-13% of deaths in different parts of the world. At its core, obesity is a multifactorial, low-grate chronic inflammatory illness of energy balance, bodyweight being steady when energy is balanced. Morbid energy balance is when the amount of energy consumed as food and drink exceeds the energy used. For instance, an adult on average consumption of 20 kcal a day more than she/he expends, leading to an average weight gain of 1 kg a year, whereas eating 100 kcal a day more than expending, gain up to 5 kg a year [1]. In effect, any intervention that changes such a morbid energy balance may be effective in the prevention and therapy of obesity and related cardiometabolic diseases (CMD) such as atherosclerois, hypertension, type 2 diabetes mellitus, and metabolic syndrome. Here we focus on (i) Homo obesus as a metabotrophin-deficient species, (ii) metabotrophin-targeted pharmacology, and (iii) adiponutrigenomics of lifespan. HOMO OBESUS: A METABOTROPHIN-DEFICIENT SPE- CIES In analogy to Rita Levi-Montalcini s terminology for neurotrophic factors and neurotrophins [reviewed in 2], the terms metabotrophic factors (metabotrophins) are coined for a group of endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing [3,4]. Man the obese, herein dubbed Homo obesus, is at high risk of multiple health problems and needs full medical management. In the last years, Homo obesus, like Diogenes (c B.C.), increasingly says I am a citizen of the world, thus pointing to the global nature of obesity. Recent studies provide evidence that morbid obesity is a major evil of human health, because plays a pivotal role in the development of CMD as well as nonalcoholic steatohepatitis, obstructive sleep apnea syndrome, polycystic ovary syndrome [1-15] and Alzheimer s disease [16,17]. Specifically, Homo *Address correspondence to this author at the Division of Cell Biology, Medical University, BG-9002 Varna, Bulgaria; chaldakov@yahoo.com obesus is herein described as a metabotrophin-deficient species; a selected list of metabotrophic factors is presented in Table 1. Whether the Israeli sand rat Psammomys obesus, a well-known animal model of obesity, type 2 diabetes and metabolic syndrome, is, like Homo obesus, a metabotrophin-deficient species remains to be studied.!able 1. Secretory proteins Endogenous Metabotrophic Factors Adiponectin [5,9,10,28,42] NGF [2-7,12,18] BDNF [2,18-21,41,47-49] Angiopoietin-like protein 4 [13], IL-10, IL-1 receptor antagonist* Ciliary neurotrophic factor* Glial cell line-derived neurotrophic factor* Bone morphogenetic protein-9* Leukemia inhibitory factor* Metallothionein-I, -II* Incretins (glucagon-like protein-1, glucose-dependent insulinotropic protein) [26,27] Intracellular proteins Sirtuins [33-39] Peroxisome proliferator-activated receptor-gamma [42] Aquaporin-7 (AQP7)**, AQP9** [44-46] Glucose transporters [50] Uncoupling proteins [51,52] * See [2-4 and references therein]. ** Discovered firstly by Gheorghe Benga as a water channel protein of plasma membrane of erythrocytes [reviewed in 44], this family of proteins includes today 13 members, AQP-7 and AQP9 being aquaglyceroporins in adipocytes and hepatocytes, respectively. AQP7 gene knockout mice develop insulin resistance and obesity. Both AQP7 and AQP9 may be new pharmacological targets in obesity and related diseases [45,46]. METABOTROPHIN-TARGETED PHARMACOLOGY Endogenous Metabotrophic Factors According to current paradigms, obesity and related CMD are associated with elevated systemic and/or local levels of proinflammatory and thrombogenic mediators, such as tumor necrosis factoralpha (TNF-!), hypoxia inducible factor-1!, interleukin-1 (IL-1), /07 $ Bentham Science Publishers Ltd. 4
9 2176 Current Pharmaceutical Design, 2007, 13, Homo obesus: A Metabotrophin-Deficient Species. Pharmacology and Nutrition Insight G.N. Chaldakov 1,3,*, M. Fiore 2, A.B. Tonchev 1,3, D. Dimitrov 3, R. Pancheva 3, G. Rancic 4 and L. Aloe 2 1 Division of Cell Biology, Medical University, Varna, Bulgaria, 2 Institute of Neurobiology, National Research Council-European Brain Research Institute, NGF Section, Rome, Italy, 3 Nutrigenomics Center, Medical University, Varna, Bulgaria and 4 Department of Histology and Embriology, Medical Faculty, Nis, Serbia Abstract: In most countries the prevalence of obesity now exceeds 15%, the figure used by the World Health Organization to define the critical threshold for intervention in nutritional epidemics. Here we describe Homo obesus (man the obese) as a recent phenotypic expression of Homo sapiens. Specifically, we classified Homo obesus as a species deficient of metabotrophic factors (metabotrophins), including endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing. Here we propose that pharmaceuticals, nutraceuticals and xenohormetics targeting transcriptional, secretory and/or signaling pathways of metabotrophins, particularly adiponectin, nerve growth factor, brain-derived neurotrophic factor, interleukin-10, and sirtuins, might be new tools for therapy of Homo obesus. Brief comment is also given to (i) exogenous metabotrophic agents represented by various classes of drugs, and (ii) adiponutrigenomics of lifspan. Key words: Metabotrophins, metabotrophin-targeted pharmacology. When someone declared that life is an evil, Diogenes said: Not life itself, but living ill. INTRODUCTION Obesity is one of the greatest public health challenges of the 21st century. Obesity is already responsible for 2-8% of health costs and 10-13% of deaths in different parts of the world. At its core, obesity is a multifactorial, low-grate chronic inflammatory illness of energy balance, bodyweight being steady when energy is balanced. Morbid energy balance is when the amount of energy consumed as food and drink exceeds the energy used. For instance, an adult on average consumption of 20 kcal a day more than she/he expends, leading to an average weight gain of 1 kg a year, whereas eating 100 kcal a day more than expending, gain up to 5 kg a year [1]. In effect, any intervention that changes such a morbid energy balance may be effective in the prevention and therapy of obesity and related cardiometabolic diseases (CMD) such as atherosclerois, hypertension, type 2 diabetes mellitus, and metabolic syndrome. Here we focus on (i) Homo obesus as a metabotrophin-deficient species, (ii) metabotrophin-targeted pharmacology, and (iii) adiponutrigenomics of lifespan. HOMO OBESUS: A METABOTROPHIN-DEFICIENT SPE- CIES In analogy to Rita Levi-Montalcini s terminology for neurotrophic factors and neurotrophins [reviewed in 2], the terms metabotrophic factors (metabotrophins) are coined for a group of endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing [3,4]. Man the obese, herein dubbed Homo obesus, is at high risk of multiple health problems and needs full medical management. In the last years, Homo obesus, like Diogenes (c B.C.), increasingly says I am a citizen of the world, thus pointing to the global nature of obesity. Recent studies provide evidence that morbid obesity is a major evil of human health, because plays a pivotal role in the development of CMD as well as nonalcoholic steatohepatitis, obstructive sleep apnea syndrome, polycystic ovary syndrome [1-15] and Alzheimer s disease [16,17]. Specifically, Homo *Address correspondence to this author at the Division of Cell Biology, Medical University, BG-9002 Varna, Bulgaria; chaldakov@yahoo.com obesus is herein described as a metabotrophin-deficient species; a selected list of metabotrophic factors is presented in Table 1. Whether the Israeli sand rat Psammomys obesus, a well-known animal model of obesity, type 2 diabetes and metabolic syndrome, is, like Homo obesus, a metabotrophin-deficient species remains to be studied.!able 1. Secretory proteins Endogenous Metabotrophic Factors Adiponectin [5,9,10,28,42] NGF [2-7,12,18] BDNF [2,18-21,41,47-49] Angiopoietin-like protein 4 [13], IL-10, IL-1 receptor antagonist* Ciliary neurotrophic factor* Glial cell line-derived neurotrophic factor* Bone morphogenetic protein-9* Leukemia inhibitory factor* Metallothionein-I, -II* Incretins (glucagon-like protein-1, glucose-dependent insulinotropic protein) [26,27] Intracellular proteins Sirtuins [33-39] Peroxisome proliferator-activated receptor-gamma [42] Aquaporin-7 (AQP7)**, AQP9** [44-46] Glucose transporters [50] Uncoupling proteins [51,52] * See [2-4 and references therein]. ** Discovered firstly by Gheorghe Benga as a water channel protein of plasma membrane of erythrocytes [reviewed in 44], this family of proteins includes today 13 members, AQP-7 and AQP9 being aquaglyceroporins in adipocytes and hepatocytes, respectively. AQP7 gene knockout mice develop insulin resistance and obesity. Both AQP7 and AQP9 may be new pharmacological targets in obesity and related diseases [45,46]. METABOTROPHIN-TARGETED PHARMACOLOGY Endogenous Metabotrophic Factors According to current paradigms, obesity and related CMD are associated with elevated systemic and/or local levels of proinflammatory and thrombogenic mediators, such as tumor necrosis factoralpha (TNF-!), hypoxia inducible factor-1!, interleukin-1 (IL-1), /07 $ Bentham Science Publishers Ltd. 4
10 2176 Current Pharmaceutical Design, 2007, 13, Homo obesus: A Metabotrophin-Deficient Species. Pharmacology and Nutrition Insight G.N. Chaldakov 1,3,*, M. Fiore 2, A.B. Tonchev 1,3, D. Dimitrov 3, R. Pancheva 3, G. Rancic 4 and L. Aloe 2 1 Division of Cell Biology, Medical University, Varna, Bulgaria, 2 Institute of Neurobiology, National Research Council-European Brain Research Institute, NGF Section, Rome, Italy, 3 Nutrigenomics Center, Medical University, Varna, Bulgaria and 4 Department of Histology and Embriology, Medical Faculty, Nis, Serbia Abstract: In most countries the prevalence of obesity now exceeds 15%, the figure used by the World Health Organization to define the critical threshold for intervention in nutritional epidemics. Here we describe Homo obesus (man the obese) as a recent phenotypic expression of Homo sapiens. Specifically, we classified Homo obesus as a species deficient of metabotrophic factors (metabotrophins), including endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing. Here we propose that pharmaceuticals, nutraceuticals and xenohormetics targeting transcriptional, secretory and/or signaling pathways of metabotrophins, particularly adiponectin, nerve growth factor, brain-derived neurotrophic factor, interleukin-10, and sirtuins, might be new tools for therapy of Homo obesus. Brief comment is also given to (i) exogenous metabotrophic agents represented by various classes of drugs, and (ii) adiponutrigenomics of lifspan. Key words: Metabotrophins, metabotrophin-targeted pharmacology. When someone declared that life is an evil, Diogenes said: Not life itself, but living ill. INTRODUCTION Obesity is one of the greatest public health challenges of the 21st century. Obesity is already responsible for 2-8% of health costs and 10-13% of deaths in different parts of the world. At its core, obesity is a multifactorial, low-grate chronic inflammatory illness of energy balance, bodyweight being steady when energy is balanced. Morbid energy balance is when the amount of energy consumed as food and drink exceeds the energy used. For instance, an adult on average consumption of 20 kcal a day more than she/he expends, leading to an average weight gain of 1 kg a year, whereas eating 100 kcal a day more than expending, gain up to 5 kg a year [1]. In effect, any intervention that changes such a morbid energy balance may be effective in the prevention and therapy of obesity and related cardiometabolic diseases (CMD) such as atherosclerois, hypertension, type 2 diabetes mellitus, and metabolic syndrome. Here we focus on (i) Homo obesus as a metabotrophin-deficient species, (ii) metabotrophin-targeted pharmacology, and (iii) adiponutrigenomics of lifespan. HOMO OBESUS: A METABOTROPHIN-DEFICIENT SPE- CIES In analogy to Rita Levi-Montalcini s terminology for neurotrophic factors and neurotrophins [reviewed in 2], the terms metabotrophic factors (metabotrophins) are coined for a group of endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing [3,4]. Man the obese, herein dubbed Homo obesus, is at high risk of multiple health problems and needs full medical management. In the last years, Homo obesus, like Diogenes (c B.C.), increasingly says I am a citizen of the world, thus pointing to the global nature of obesity. Recent studies provide evidence that morbid obesity is a major evil of human health, because plays a pivotal role in the development of CMD as well as nonalcoholic steatohepatitis, obstructive sleep apnea syndrome, polycystic ovary syndrome [1-15] and Alzheimer s disease [16,17]. Specifically, Homo *Address correspondence to this author at the Division of Cell Biology, Medical University, BG-9002 Varna, Bulgaria; chaldakov@yahoo.com obesus is herein described as a metabotrophin-deficient species; a selected list of metabotrophic factors is presented in Table 1. Whether the Israeli sand rat Psammomys obesus, a well-known animal model of obesity, type 2 diabetes and metabolic syndrome, is, like Homo obesus, a metabotrophin-deficient species remains to be studied.!able 1. Secretory proteins Endogenous Metabotrophic Factors Adiponectin [5,9,10,28,42] NGF [2-7,12,18] BDNF [2,18-21,41,47-49] Angiopoietin-like protein 4 [13], IL-10, IL-1 receptor antagonist* Ciliary neurotrophic factor* Glial cell line-derived neurotrophic factor* Bone morphogenetic protein-9* Leukemia inhibitory factor* Metallothionein-I, -II* Incretins (glucagon-like protein-1, glucose-dependent insulinotropic protein) [26,27] Intracellular proteins Sirtuins [33-39] Peroxisome proliferator-activated receptor-gamma [42] Aquaporin-7 (AQP7)**, AQP9** [44-46] Glucose transporters [50] Uncoupling proteins [51,52] * See [2-4 and references therein]. ** Discovered firstly by Gheorghe Benga as a water channel protein of plasma membrane of erythrocytes [reviewed in 44], this family of proteins includes today 13 members, AQP-7 and AQP9 being aquaglyceroporins in adipocytes and hepatocytes, respectively. AQP7 gene knockout mice develop insulin resistance and obesity. Both AQP7 and AQP9 may be new pharmacological targets in obesity and related diseases [45,46]. METABOTROPHIN-TARGETED PHARMACOLOGY Endogenous Metabotrophic Factors According to current paradigms, obesity and related CMD are associated with elevated systemic and/or local levels of proinflammatory and thrombogenic mediators, such as tumor necrosis factoralpha (TNF-!), hypoxia inducible factor-1!, interleukin-1 (IL-1), /07 $ Bentham Science Publishers Ltd. 4
11 Vi kan ikke klare moderne levevis! Cordain L, Eaton BS, Sebastian A et al. Origins and evolution of the Western diet: helath implications for the 21st century. Am J Clin Nutr 2005;81:
12 Evolutionær arv og behov Rigtig mad Grøntsager, bær, frugter, fisk, skaldyr, nødder, frø, kerner, (vilde) dyr og ægte fedt Daglig bevægelse Søvn Perioder med ro i informationsstrømmen Tilhørsforhold i en flok eller gruppe 6
13 The Blue Zones Study 7
14 The Blue Zones Daniel Buettner - opdagelsesrejsende og forsker har skrevet den fantastiske bog The Blue Zone Story. Forskere har talt om Blue Zones siden de fandt en bjerglandsby i Sardinien hvor uhørt mange mænd blev 100 år gamle "Blue zones" er de områder i verden, hvor folk lever længere og har mindre sygdom. Altså de steder, hvor befolkningen oplever succesfuld aldring og et langt sundt og vitalt liv Mange flere lever til en alder af 100 og uden sygdom 8
15 Hvorhenne? Forskere er optaget af 7-dags adventisterne i Loma Linda i CA, USA Sardinien Okinawa i Japan Nicoya i Costa Rica Icaria i Grækenland 9
16 10
17 The Blue Zone Story Spis til du er 80% mæt. Flere grøntsager og mindre animalsk protein og raffineret mad. Udendørs dyr Drik rødvin i moderation og gør det regelmæssigt. Bevæg dig, f.eks. ved at være i et miljø, hvor du ikke kan undgå at bevæge dig som en del af din dagligdag. Få nok søvn (og gerne en kort middagslur) og husk i det hele taget at slappe af 11
18 The Blue Zone story "Plan de Vida" (hav et formål med dit liv) Hav et tilhørsforhold (dit sociale netværk) Tro (åndelighed, spiritualitet, religion) "Din stamme" (familiesammenhold) 12
19 Online Dan Buettner om Grækenland i National Geographic Dan Buettner om de 9 hemmeligheder bag et langt liv i National Geographic 13
20 Hulemandskost og jæger-samler-samfund 14
21 Også sundhed Hvis man bortregner børnedødeligheden p.g.a. infektioner og ringe hygiejne, død p.g.a. katastrofer og hungersnød, så lever folk i jæger-samler samfund meget længe og med en høj grad af vitalitet De lever også på en måde, der minder meget om folk fra Blue Zones Bevægelse, masser af planter, samfund og sammenhold, spiritualitet, værdi for andre og familiært sammenhold samt respekt for mad og måltidet Desuden animalske kalorier! Men vilde 15
22 Hvad holder ikke? 16
23 Er korn farlige? Nej ikke som udgangspunkt! Spiser vi ofte for mange i forhold til muskelmasse og aktivitetsniveau? Spiser vi i gennemsnit for mange raffinerede? Er der enkeltpersoner, der ikke tåler gluten og/eller har andre problemer med korn? 17
24 Cøliaki 1-5% af befolkningen i vestlige lande 18
25 Andre issues Gluten kan spille en rolle i autisme og ADHD Gluten kan spille en rolle i gigtsygdomme Gluten kan spille en rolle i Hashimoto s Gluten kan spille en rolle i IBS Andre stoffer i korn kan virke irriterende på tarmslimhinden 19
26 Er insulin ondt? 20
27 Den rette mængder og periodisk Der skal hverken være for meget eller for lidt insulin Der skal ikke være insulin non-stop Gavnlige effekter Thermogenese, regulering af blodsukker, anabolsk effekt, neurologiske effekter, anti-inflammatorisk Skadevirkninger Inflammation, uønsket vækst, påvirkning af kønshormoner, forstyrret forbrænding, neurologisk 21
28 Er mælk ondt og mejeriprodukter onde? Nej Men de er heller ikke nødvendige Der er andre kilder til kalk Mælk nu og dengang er ikke det samme Færre omega-3 fedtsyrer Mindre D-vitamin og K-vitamin Mindre jod? 22
29 Potentielle issues Kan spille en rolle i autisme og ADHD på samme maner som gluten Kan spille en rolle i øre-næse-hals-problemer og astma Kan spille en rolle i fordøjelsesproblemer Laktoseintolerance nok mere end 2-4% af befolkningen Er en vækstfaktor issue i allerede etableret cancer? 23
30 24
31 Er bælgfrugter onde? 25
32 Bælgfrugter er en del af kosten i Blue Zones! God kilde til protein, meget laaangsom stivelse og fibre En af de bedste kilder af folsyre pr. kalorie God kilde af magnesium, jern og visse B-vitaminer Mørke bælgfrugter indeholder antioxidanter der er på niveau med dem i vin og bær 26
33 27
34 Hvad med lektinerne? Værd at være opmærksomme på ved mavetarmproblemer og kroniske tilstande hvor øget tarmpermeabilitet kan spille en rolle IBS IBD Gigttilstande med en autoimmun komponent Neuro-psykiatriske problemer med en gastrointestinal komponent 28
35 Thomas Rode 29
36 30
37 31
38 Case 2 32
39 33
40 33
41 Case 3 34
42 35
43 35
44 Konklusioner 36
45 Et redskab Stenalder/palæo/jæger-samler/ oprindelig kost er et redskab Brug det når det er relevant og nødvendigt Det virker for nogle hvor andre sunde kostformer ikke har virket Brug det til at finde frem til, hvad der virker for dig 37
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