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DOI: 10.1055/s-2007-970828
Prävention von Krankheiten und Steigerung der Lebenserwartung durch Kalorienrestriktion
Calorie Restriction Mediates Increased Disease Resistance and Life ExpectancyPublication History
Publication Date:
09 May 2007 (online)
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Zusammenfassung
Seneszenz reflektiert die biologische Summe schadhafter Einflüsse, die im Laufe des Lebens akkumulieren, und zu der Entstehung alterungsbedingter Erkrankungen, wie zum Beispiel Diabetes mellitus, Herz-Kreislauf-Erkrankungen, neurodegenerativen Erkrankungen und Krebs beitragen. Eine wichtige Begleiterscheinung des Alterungsprozesses ist die schrittweise Beeinträchtigung der mitochondrialen Nährstoffkonversion. Aktuelle Forschungsergebnisse legen dementsprechend einen Zusammenhang zwischen gestörtem mitochondrialen Energiestoffwechsel und der Entstehung altersassoziierter Erkrankungen nahe. Im Umkehrschluss könnte eine Steigerung der mitochondrialen Energiegewinnung positiven Einfluss auf Aspekte der zellulären und systemischen Seneszenz nehmen, und der Entwicklung metabolischer Erkrankungen entgegenwirken; die Untersuchung ihrer biochemischen Ursachen und mechanistischen Grundlagen sind daher zentrale Ziele der Alterungsforschung. Mit Hinblick auf die steigende Inzidenz metabolischer Erkrankungen in den westlichen Gesellschaften ist daher eine übergreifende Kenntnis der molekularen Regulation des mitochondrialen Energiestoffwechsels von besonderer klinischer Relevanz.
Abstract
Senescence reflects the biological sum of deteriorating influences that accumulate during life span and promote the development of ageing-associated diseases such as the diabetes mellitus, cardiovascular diseases, neurodegenerative disorders, and cancer. A prominent by-effect of the ageing process is the progressive reduction of mitochondrial nutrient conversion. Hence, the positive correlation between dysfunctional mitochondrial energy metabolism and disease at high age suggests a significant impact of the mitochondrion in the signalling events leading to these perturbations. In return, activation of mitochondrial bioenergetic efficiency could exert beneficial effects on cellular and systemic senescence and counteract the development of metabolic illness. The investigation of biochemical mechanisms underlying the ageing process remain central aims of gerontology. With regard to the ever increasing incidence of metabolic disease in Westernised societies, a comprehensive understanding of biochemical regulation of oxidative energy metabolism in the mitochondrion is therefore warranted and of particular clinical relevance.
Schlüsselwörter
Alterung - Kalorienrestriktion - Lebenserwartung - Mitochondrien - Stoffwechsel - Krebs - Diabetes - Übergewicht - Neurodegeneration
Key words
aging - calorie restriction - life span - life expectancy - mitochondria - metabolism - cancer - diabetes - obesity - neurodegeneration
Literatur
-
1 Rubner III M.
Das Wachstumsproblem und die Lebensdauer des Menschen und einiger Säugetiere vom energetischen Standpunkt aus betrachtet. In: Rubner M (Hrsg) Das Problem der Lebensdauer und seine Beziehungen zum Wachstum und der Ernährung. Munich, Berlin; R. Oldenbourg 1908: pp 127-208 - 2 Pearl R. The rate of living. Being an account of some experimental studies on the biology of life duration. New York; Alfred Knopf 1928
- 3 Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956; 11 (3) 298-300
- 4 Balaban R S, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005; 120 (4) 483-495
- 5 Gutteridge J M, Halliwell B. The measurement and mechanism of lipid peroxidation in biological systems. Trends Biochem Sci. 1990; 15 (4) 129-135
- 6 Dizdaroglu M. Oxidative damage to DNA in mammalian chromatin. Mutat Res. 1992; 275 (3 - 6) 331-342
- 7 Flint D H, Tuminello J F, Emptage M H. The inactivation of Fe-S cluster containing hydro-lyases by superoxide. J Biol Chem. 1993; 268 (30) 22369-22376
- 8 Andziak B, O'Connor T P, Qi W, DeWaal E M, Pierce A, Chaudhuri A R, Remmen H Van, Buffenstein R. High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell. 2006; 5 (6) 463-471
- 9 Brand M D. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol. 2000; 35 (6 - 7) 811-820
- 10 Stryer L. Biochemistry. New York; W. H. Freeman and company 1995
- 11 Fridell Y W, Sanchez-Blanco A, Silvia B A, Helfand S L. Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab. 2005; 1 (2) 145-152
- 12 Speakman J R, Talbot D A, Selman C, Snart S, McLaren J S, Redman P, Krol E, Jackson D M, Johnson M S, Brand M D. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell. 2004; 3 (3) 87-95
- 13 Southam C M, Ehrlich J. Effects of extract of western red-cedar heartwood on certain wood-decaying fungi in culture. Phytopathology. 1943; 33 517-524
- 14 Calabrese E J, Baldwin L A. Defining hormesis. Hum Exp Toxicol. 2002; 21 (2) 91-97
- 15 Minois N. Longevity and aging: beneficial effects of exposure to mild stress. Biogerontology. 2000; 1 (1) 15-29
- 16 Damelin L H, Vokes S, Whitcutt J M, Damelin S B, Alexander J J. Hormesis: a stress response in cells exposed to low levels of heavy metals. Hum Exp Toxicol. 2000; 19 (7) 420-430
- 17 Tapia P C. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: „mitohormesis” for health and vitality. Med Hypotheses. 2006; 66 (4) 832-843
- 18 Cook R, Calabrese E J. The importance of hormesis to public health. Environ Health Perspect. 2006; 114 (11) 1631-1635
- 19 Kharade S V, Mittal N, Das S P, Sinha P, Roy N. Mrg19 depletion increases S. cerevisiae lifespan by augmenting ROS defence. FEBS Lett. 2005; 579 (30) 6809-6813
- 20 Smith J M. Prolongation of the life of Drosophila subobscura by a brief exposure of adults to a high temperature. Nature. 1958; 181 (4607) 496-497
- 21 Cypser J, Johnson T E. Hormesis extends the correlation between stress resistance and life span in long-lived mutants of Caenorhabditis elegans. Hum Exp Toxicol. 2001; 20 (6) 295-296, discussion 319 - 320
- 22 Caratero A, Courtade M, Bonnet L, Planel H, Caratero C. Effect of a continuous gamma irradiation at a very low dose on the life span of mice. Gerontology. 1998; 44 (5) 272-276
- 23 Rattan S I. Applying hormesis in aging research and therapy. Hum Exp Toxicol. 2001; 20 (6) 281-285, discussion 293 - 294
- 24 Weindruch R, Walford R L. The retardation of aging and disease by dietary restriction. Springfield, Illinois; Charles C Thomas Pub Ltd 1988
- 25 Sinclair D A. Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev. 2005; 126 (9) 987-1002
- 26 Petersen K F, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman D L, DiPietro L, Cline G W, Shulman G I. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003; 300 (5622) 1140-1142
- 27 Lin M T, Beal M F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006; 443 (7113) 787-795
- 28 Guarente L, Picard F. Calorie restriction - the SIR2 connection. Cell. 2005; 120 (4) 473-482
- 29 Kaeberlein M, Kirkland K T, Fields S, Kennedy B K. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2004; 2 (9) E296
- 30 Nemoto S, Fergusson M M, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem. 2005; 280 (16) 16456-16460
- 31 Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo M V, Allard J, Ingram D K, Navas P, Cabo R de. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA. 2006; 103 (6) 1768-1773
- 32 St-Pierre J, Drori S, Uldry M, Silvaggi J M, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon D K, Bachoo R, Spiegelman B M. Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators. Cell. 2006; 127 (2) 397-408
- 33 Beckman K B, Ames B N. The free radical theory of aging matures. Physiol Rev. 1998; 78 (2) 547-581
- 34 Magalhaes J P de, Church G M. Cells discover fire: employing reactive oxygen species in development and consequences for aging. Exp Gerontol. 2006; 41 (1) 1-10
- 35 Oliveira R L, Ueno M, Souza C T de, Pereira-da-Silva M, Gasparetti A L, Bezzera R M, Alberici L C, Vercesi A E, Saad M J, Velloso L A. Cold-induced PGC-1alpha expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway. Am J Physiol Endocrinol Metab. 2004; 287 (4) E686-695
- 36 Dilman V M, Anisimov V N. Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C3H/Sn mice. Gerontology. 1980; 26 (5) 241-246
- 37 Apfeld J, O'Connor G, McDonagh T, DiStefano P S, Curtis R. The AMP-activated protein kinase aak-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 2004; 18 (24) 3004-3009
- 38 Ristow M, Mulder H, Pomplun D, Schulz T J, Müller-Schmehl K, Krause A, Fex M, Puccio H, Müller J, Isken F, Spranger J, Müller-Wieland D, Magnuson M A, Möhlig M, Koenig M, Pfeiffer A FH. Frataxin-deficiency in pancreatic islets causes diabetes due to loss of beta-cell mass. J Clin Invest. 2003; 112 (4) 527-534
- 39 Kelley D E, He J, Menshikova E V, Ritov V B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002; 51 (10) 2944-2950
- 40 Pomplun D, Voigt A, Schulz T J, Thierbach R, Pfeiffer A FH, Ristow M. Reduced expression of mitochondrial frataxin in mice exacerbates diet-induced obesity. Proc Nat Acad Sci. 2007; 104 (15) 6377-6381
- 41 Lowell B B, Shulman G I. Mitochondrial dysfunction and type 2 diabetes. Science. 2005; 307 (5708) 384-387
- 42 Warburg O, Posener K, Negelein E. Über den Stoffwechsel der Tumoren (On metabolism of tumors). Biochemische Zeitschrift. 1924; 152 319-344
- 43 Carew J S, Huang P. Mitochondrial defects in cancer. Mol Cancer. 2002; 1 (1) 9
- 44 Petros J A, Baumann A K, Ruiz-Pesini E, Amin M B, Sun C Q, Hall J, Lim S, Issa M M, Flanders W D, Hosseini S H, Marshall F F, Wallace D C. mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA. 2005; 102 (3) 719-724
- 45 Thierbach R, Schulz T J, Isken F, Voigt A, Mietzner B, Drewes G, Kleist-Retzow J C von, Wiesner R J, Magnuson M A, Puccio H, Pfeiffer A F, Steinberg P, Ristow M. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span, and tumor growth in mice. Hum Mol Genet. 2005; 14 3857-3864
- 46 Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington S J, Capaldi R A. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res. 2004; 64 (3) 985-993
- 47 Schulz T J, Thierbach R, Voigt A, Drewes G, Mietzner B H, Steinberg P, Pfeiffer A F, Ristow M. Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J Biol Chem. 2006; 281 (2) 977-981
- 48 Houthoofd K, Braeckman B P, Lenaerts I, Brys K, Vreese A De, Eygen S Van, Vanfleteren J R. Axenic growth up-regulates mass-specific metabolic rate, stress resistance, and extends life span in Caenorhabditis elegans. Exp Gerontol. 2002; 37 (12) 1371-1378
- 49 Zarse K, Schulz T J, Birringer M, Ristow M. Impaired respiration is positively correlated with decreased life span in Caenorhabditis elegans models of Friedreich Ataxia. FASEB J online pre-print (print version scheduled for April 2007) 2007 doi DOI: 10.1096/fj.06-6994com.
- 50 Wood J G, Rogina B, Lavu S, Howitz K, Helfand S L, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004; 430 (7000) 686-689
- 51 Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1alpha. Cell. 2006; 127 (6) 1109-1122
- 52 Baur J A, Pearson K J, Price N L, Jamieson H A, Lerin C, Kalra A, Prabhu V V, Allard J S, Lopez-Lluch G, Lewis K, Pistell P J, Poosala S, Becker K G, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein K W, Spencer R G, Lakatta E G, Couteur D Le, Shaw R J, Navas P, Puigserver P, Ingram D K, Cabo R de, Sinclair D A. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006; 444 (7117) 357-392
- 53 Ingram D K, Zhu M, Mamczarz J, Zou S, Lane M A, Roth G S, Cabo R de. Calorie restriction mimetics: an emerging research field. Aging Cell. 2006; 5 (2) 97-108
- 54 Zhu Z, Jiang W, McGinley J N, Thompson H J. 2-Deoxyglucose as an energy restriction mimetic agent: effects on mammary carcinogenesis and on mammary tumor cell growth in vitro. Cancer Res. 2005; 65 (15) 7023-7030
- 55 Stattin P, Bjor O, Ferrari P, Lukanova A, Lenner P, Lindahl B, Hallmans G, Kaaks R. Prospective study of hyperglycemia and cancer risk. Diabetes Care. 2007; 30 (3) 561-567
- 56 Fontana L, Klein S. Aging, adiposity, and calorie restriction. JAMA. 2007; 297 (9) 986-994
- 57 Roth G S, Mattison J A, Ottinger M A, Chachich M E, Lane M A, Ingram D K. Aging in rhesus monkeys: relevance to human health interventions. Science. 2004; 305 (5689) 1423-1426
- 58 Ingram D K, Roth G S, Lane M A, Ottinger M A, Zou S, Cabo R de, Mattison J A. The potential for dietary restriction to increase longevity in humans: extrapolation from monkey studies. Biogerontology. 2006; 7 (3) 143-148
- 59 Lane M A, Ingram D K, Roth G S. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicol Sci. 1999; 52 (2 Suppl) 41-48
- 60 Hindhede M. The effects of food restriction during war on mortality in Copenhagen. JAMA. 1921; 74 381-382
- 61 Strom A, Jensen R A. Mortality from circulatory diseases in Norway 1940 - 1945. Lancet. 1951; 1 (3) 126-129
- 62 Kagawa Y. Impact of Westernization on the nutrition of Japanese: changes in physique, cancer, longevity and centenarians. Prev Med. 1978; 7 (2) 205-217
- 63 Bik W, Baranowska-Bik A, Wolinska-Witort E, Martynska L, Chmielowska M, Szybinska A, Broczek K, Baranowska B. The relationship between adiponectin levels and metabolic status in centenarian, early elderly, young and obese women. Neuro Endocrinol Lett. 2006; 27 (4) 493-500
- 64 Wei E K, Giovannucci E, Fuchs C S, Willett W C, Mantzoros C S. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst. 2005; 97 (22) 1688-1694
- 65 Heilbronn L K, Jonge L de, Frisard M I, DeLany J P, Larson-Meyer D E, Rood J, Nguyen T, Martin C K, Volaufova J, Most M M, Greenway F L, Smith S R, Deutsch W A, Williamson D A, Ravussin E. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006; 295 (13) 1539-1548
- 66 Fontana L. Excessive adiposity, calorie restriction, and aging. JAMA. 2006; 295 (13) 1577-1578
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