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AHS Slides_Pedro Bastos AHS Slides_Pedro Bastos Presentation Transcript

  • MILK, DAIRY AND HUMAN HEALTHLos Angeles, August 2011 Pedro Carrera Bastos
  • HISTORY OF MILK & DAIRY
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  • ists (Table 2)26,67–69 when compared with current optimal 8. Lo values defined by health institutions ( 120 mm Hg parTable 1 Historical milestones in human generations14,63–65 Table YanomHistorical milestones Generations % totalHomo habilis 76,667 100.0 Age (yeHomo erectus 60,000 78.2 0–9Modern Homo sapiens 6666 8.7 10–19Neolithic Revolution 366 0.48 20–29Industrial Revolution 7 0.009 30–39Food industry (junk food) and 4 0.005 40–49physical inactivity (Modern Age) 5016 submit your manuscript | www.dovepress.com Carrera-Bastos P, Fontes-Villalba M, OKeefe JH, Lindeberg S, Cordain L. Res Rep Clin Cardiol 2011;2:15-35. Dovepress
  • EVIDENCE FOR THE USE OF DAIRY IN THE MIDDLE EAST & EUROPE First  evidence  of  dairying  in  North.  Eur  (UK)  6   First  evidence  of  dairying  in  Europe  (Romania)  5   First  evidence  of  dairying  in  the  Middle  East  (Turkey)  4   Domes@ca@on  of  sheeps,  goats  and  caBle  (Middle  East)  1-­‐3   PresentGenerations Human 333 300 267 233 200 167 133 100 66 33 1 - Hiendleder S, et al. Proc Biol Sci. 2002 May 7;269(1494):893-904 2 - Luikart G, et al. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5927-32 3 - Loftus RT, et al. Mol Ecol. 1999 Dec;8(12):2015-22 4 - Evershed RP et al. Nature. 2008 Sep 25;455(7212):528-31. 5 - Craig OE, et al. Antiquity 2005; 79:882-894 6 - Copley MS et al. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1524-9
  • 0° 45° E 90° E 135° E 180° E ALP IN EUROPE " (b) 60° N 0.9 0.8 0.7 30° N 0.6 0.5 0° 0.4 0.3 0.2 30° S 0.1 Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77. 0° 45° E 90° E 135° E 180° Egure 1. Interpolated maps of the distribution of LP and the 213910*T allele in the ‘old world’. (a) LP phenotype di tion. Data points (dots) Old World LP phenotype frequencies based on -13,910 C>T Distribution of the a Predicted were taken from the literature (see text and [14] for details). (b) allele frequency data only13910*T, associated to LP. Dots represent sample data taken from a previous review [14,26–30]; crosses representr new locations not previously tested and diamonds correspond to locations where additional data have been add Dates of origin: between 2188 and 20650 BP gularly updated frequency data are available at http://www.ucl.ac.uk//mace-lab/GLAD/ website. and between 7450 and 12300 BPequency of Somali people living in Ethiopia does not necessarily have conferred any selective advanta event them from drinking more than 500 ml of milk The culture-historical hypothesis is better suppor
  • ARTICLE Independent Introduction of Two Lactase-Persistence Alleles into Human Populations Reflects Different History of Adaptation to Milk Culture Nabil Sabri Enattah,1,2 Tine G.K. Jensen,3 Mette Nielsen,3 Rikke Lewinski,3 Mikko Kuokkanen,1,2 Heli Rasinpera,1,2 Hatem El-Shanti,4 Jeong Kee Seo,5 Michael Alifrangis,6 Insaf F. Khalil,6 Abdrazak Natah,7 Ahmed Ali,9 Sirajedin Natah,8 David Comas,10 S. Qasim Mehdi,11 Leif Groop,12 Else Marie Vestergaard,13 Faiqa Imtiaz,14 Mohamed S. Rashed,15 Brian Meyer,14 Jesper Troelsen,3 and Leena Peltonen1,2,* The TÀ13910 variant located in the enhancer element of the lactase (LCT) gene correlates perfectly with lactase persistence (LP) in Eur- asian populations whereas the variant is almost nonexistent among Sub-Saharan African populations, showing high prevalence of LP. Here, we report identification of two new mutations among Saudis, also known for the high prevalence of LP. We confirmed the ab-Domestication of the Arabian camel: 6000 BP sence of the European TÀ13910 and established two new mutations found as a compound allele: T/GÀ13915 within the À13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/CÀ3712, À3712 bp from the LCT gene. The compound allele is driven to a high prevalence among Middle East population(s). Our functional analyses in vitro showed that both SNPs of the compound allele, located 10 kb apart, are required for the enhancer effect, most probably mediated through the binding of the hepatic nuclear factor 1 a (HNF1a). High selection coefficient (s) ~0.04 for LP phenotype was found for both TÀ13910 and the compound allele. The European TÀ13910 and the earlier identified East African GÀ13907 LP allele share the same ancestral background and most likely the same history, probably related to the same cattle domestication event. In contrast, the compound Arab allele shows a different, highly divergentOrigin of G -13915 allele in the Arabian Pensinsula: 4000 BP ancestral haplotype, suggesting that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption. These results support the convergent evolution of the LP in diverse populations, most probably reflecting different histories of adaptation to milk culture. Introduction that the LP trait-related TÀ13910 allele binds Oct-1 tran- scription factor more strongly than does the CÀ13910 allele. The dairy culture was initiated some 10,000 years ago in It has been further demonstrated that a wider DNA region the Middle East with the domestication of sheep, goat, encompassing the C/TÀ13910 variant contains an enhancer and cattle.1–4 Lactase activity of intestinal cells, responsible element with binding sites for several transcription fact- for the digestion of the milk sugar, lactose, declines after ors such as Oct-1 and GATA-6 (region from À13909 weaning for most humans.5 However, in multiple global to À13934), HNF4a and Fox/HNF3a (region À13857 Enattah NS, et al. Am J Hum Genet. 2008 Jan;82(1):57-72 subpopulations, a genetic capacity of adult humans to di- to À13817), and Cdx-2 (region À14022 to À14032). All gest milk sugar has evolved that results in the continuing these factors probably contribute to the regulation of the 10 expression of lactase by intestinal cells, a condition known lactase gene in intestinal cells. Furthermore, the expres- as lactase persistence (LP) (MIM 223000).5 We and others sion of Oct-1 has been shown to drive the reporter gene have shown that a single allele, carrying the TÀ13910 vari- expression from both TÀ13910 and CÀ13910 variant/LCT
  • Convergent adaptation of human lactase persistence© 2007 Nature Publishing Group http://www.nature.com/naturegenetics in Africa and Europe Sarah A Tishkoff1,9, Floyd A Reed1,9, Alessia Ranciaro1,2, Benjamin F Voight3, Courtney C Babbitt4, Jesse S Silverman4, Kweli Powell1, Holly M Mortensen1, Jibril B Hirbo1, Maha Osman5, Muntaser Ibrahim5, Sabah A Omar6, Godfrey Lema7, Thomas B Nyambo7, Jilur Ghori8, Suzannah Bumpstead8, Jonathan K Pritchard3, Gregory A Wray4 & Panos Deloukas8 A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype- phenotype association study in 470 Tanzanians, Kenyans and Sudanese and identified three SNPs (G/C-14010, T/G-13915 and C/G-13907) that are associated with lactase persistence and that have derived alleles that significantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending 42.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past B7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits—animal domestication and adult milk consumption. Spread of Pastoralism south of the Sahara: 4,500 BP In most humans, the ability to digest lactose, the main carbohydrate lactase persistence trait: C/T-13910 and G/A-22018, located B14 kb present in milk, declines rapidly after weaning because of decreasing and B22 kb upstream of LCT, respectively, within introns 9 and 13 of levels of the enzyme lactase-phlorizin hydrolase (LPH). LPH is the adjacent minichromosome maintenance 6 (MCM6) gene4 (Fig. 1). predominantly expressed in the small intestine, where it hydrolyzes The T-13910 and A-22018 alleles were 100% and 97% associated with lactose into glucose and galactose, sugars that are easily absorbed into lactase persistence, respectively, in the Finnish study4, and the T-13910 the bloodstream1. However, some individuals, particularly descen- allele is B86%–98% associated with lactase persistence in other Spread of Pastoralism dants from populations that have traditionally practiced cattle domes- tication, maintain the ability to digest milk and other dairy products European populations6–8. Although these alleles could simply be in LD with an unknown regulatory mutation6, several additional lines of into Northern Tanzania: 3,300 BP into adulthood. These individuals have the ‘lactase persistence’ trait. The frequency of lactase persistence is high in northern European populations (490% in Swedes and Danes), decreases in frequency evidence, including mRNA transcription studies in intestinal biopsy samples9 and reporter gene assays driven by the LCT promoter in vitro10–12, suggest that the C/T-13910 SNP regulates LCT transcrip- across southern Europe and the Middle East (B50% in Spanish, tion in Europeans. French and pastoralist Arab populations) and is low in non-pastoralist It is hypothesized that natural selection has had a major role in Asian and African populations (B1% in Chinese, B5%–20% in determining the frequencies of lactase persistence in different human West African agriculturalists)1–3. Notably, lactase persistence is com- populations since the development of cattle domestication in the mon in pastoralist populations from Africa (B90% in Tutsi, B50% Middle East and North Africa B7,500–9,000 years ago2,3,6,13–18. A in Fulani)1,3. region of extensive LD spanning 41 Mb has been observed on Lactase persistence is inherited as a dominant mendelian trait in European chromosomes with the T-13910 allele, consistent with recent Europeans1,2,4. Adult expression of the gene encoding LPH (LCT), positive selection6,14,16–18. Based on the breakdown of LD on chromo- located on 2q21, is thought to be regulated by cis-acting elements5 somes with the T-13910 allele, it is estimated14 that this allele arose (Fig. 1). A linkage disequilibrium (LD) and haplotype analysis of within the past B2,000–20,000 years within Europeans, probably in Finnish pedigrees identified two single SNPs associated with the response to strong selection for the ability to digest milk as adults. 1Department of Biology, University of Maryland, College Park, Maryland 20742, USA. 2Department of Biology, University of Ferrara, 44100 Ferrara, Italy. 3Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA. 4Institute for Genome Sciences & Policy and Department of Biology, Duke University, Durham, North Carolina 27708, USA. 5Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, 15-13 Khartoum, Sudan. 6Kenya Medical Research Institute, Centre for Biotechnology Research and Development, 54840-00200 Nairobi, Kenya. 7Department of Biochemistry, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania. 8Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. 9These authors contributed equally to this work. Correspondence should be addressed to S.A.T. (Tishkoff@umd.edu). Received 18 August; accepted 20 November; published online 10 December 2006; doi:10.1038/ng1946 NATURE GENETICS VOLUME 39 [ NUMBER 1 [ JANUARY 2007 31 Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-40
  • GG-TT-GG 1 4.59 (NA) Afro-Asiatic ALP in Africa" n = 64 Kenya Hadz (Khoisa n=1 Various SNPs associated with LP Nilo-Saharan Sandawe in Sub-Saharan Africans arose n = 126 (Khoisan) 3000-7000 BP Nilo-Saharan n = 31 n = 45 000   Afro-Asiatic n = 81dofanian Tanzania Nige Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-4061
  • The most widely consumed milk in US and Europe is cow’s milk." !! " Park YW, Haenlein GFW. Handbook of milk of non-bovine mammals. Blackwell Publishing, 2006
  • MILK PRODUCTION (Europe) Milk" 1980" 2001" Sheep" 1.9%" 1.3%" Goat" 1.0%" 1.1%" Bufalo" 0.1%" 0.1%" Cow" 97.2%" 97.5%"Park YW, Haenlein GFW. Handbook of milk of non-bovine mammals. Blackwell Publishing, 2006
  • MILK PRODUCTION PER COW (USA) Lbs25000!20000!15000!10000! 5000! 0! 1950 2010 http://quickstats.nass.usda.gov/results/79C63180-8FF4-3A0F-9CD6-D064D945F49E http://quickstats.nass.usda.gov/results/B04AD392-D39A-3C2F-A060-89A54CF5BDE1
  • RBGH INCREASES MILK PRODUCTION""" Bauman DE, Eppard PJ, DeGeeter MJ, Lanza GM. J Dairy Sci. 1985 Jun;68(6):1352-62
  • INDUSTRIAL MODEL OF DAIRYING"Change in nutritionreduced theaverage age atfirst lactation" Hare E, Norman HD, Wright JR. J Dairy Sci 2006; 89: 365-370.
  • The es Modern milking Estrone I dont know whether modern dairy farming practicesDry Japan are in I would now like hormonesunder t *Artificial insemination Pregnancy The volume of milk that was collected from this cow was 2 or 3 the same as in other developed countries. In Japan the cow is liters at most. The volume of this container is about 20 liters. that have impregnated by artificial insemination *12 to 14 months after birth. The most pregna abundant h The length of pregnancy is 280 days, the same as in humans. to a 1979 study by H contains used fo Nomadic milking After giving birth, the cow secrets colostrum. Soon after birth the 30 picogr calf is separated from its mother and the colostrum is milked by therapy concentration rises machine and given to the calf in a feeding bottle for five days. picograms in the firs last stage of pregnan These are pictures of a modern dairy farm in Japan.From the sixth day after delivery, the cow is milked every day for Nomadic milking milliliter.300 days. Two or three months after delivery, the cow is Mongolian cows feed only on grass and they do not secrete milk during the latter half of pregnancy. They get pregnant by natural from Mayinseminated artificially and gets pregnant while it is proficient in Estrone sulfate cow. ha mating in July or August, and give birth to calves in April or May. per The Mongolian nomads milk their cows for only 5 or 6 months MILK, HORMONES & HUMAN HEALTH October, 2006milk secretion. Milking is stopped for 60 days just before the next 2 body it is convertdelivery, which is referred to as the "dry period." The cow is has a high oralslaughtered after giving birth to 4 or 6 calves. Modern cows are Milk con Premarin, whichmilked for 7 or 8 months while they are pregnant, including the amount o contains naturallylatter half of pregnancy up to the dry period, which is four months pregnant mares.longer into pregnancy than Mongolian cows are milked. One final The estrocomment on Japanese Modern milking the use of Human Then,totheHarvard,and beginsOct. milk the cow forand bindsuse. dairy practices, Sato A. Health Effects of Cow Milk. Symposium on Milk, Hormones and recombinant the calf2006 the mother human the nomad separates Health,the fence Boston, to from the theUS. the the calf to here milk Estrone calfbovine growth hormone is legal in www.milksymposium.ca.orgis in Afterwardwas nomad allowscow picturedsucklewas 14again until it is Japan as it satiated. I told that years old andHowever, it is insemination dairy farmers in Japan do not use this *Artificial said that Pregnancy Dry had given birth to 10 calves.
  • “3 Cups per day of fat-free or low-fat milk and milk products”
  • 2005 DIETARY GUIDELINES ADVISORY COMMITTEE
Janet King, PhD, RD (Chair)" ! Vay Liang W. Go, MDChildren’s Hospital Oakland Research University of California at Los Angeles, LosInstitute, Oakland, CA! Angeles, CA"Lawrence J. Appel, MD, MPH" Penny M. Kris-Etherton, PhD, RDJohns Hopkins Medical Institutions, Penn State University, University Park, PABaltimore, MD!" Joanne R. Lupton, PhDYvonne L. Bronner, ScD, RD, LD" Texas A&M University, College Station, TXMorgan State University, Baltimore, MD!" Theresa A. Nicklas, DrPH, MPH, LNBenjamin Caballero, MD, PhD" Baylor College of Medicine, Houston, TXJohns Hopkins Bloomberg School of PublicHealth, Baltimore, MD! Russell R. Pate, PhD" University of South Carolina, Columbia, SCCarlos A. Camargo, MD, DrPH"Harvard University, Boston, MA! F. Xavier Pi-Sunyer, MD, MPH" Columbia University, New York, NYFergus M. Clydesdale, PhD,"University of Massachusetts, !Amherst, Connie M. Weaver, PhDAmherst, MA! Purdue University, West Lafayette, IN"Camargo C. 2005 US Dietary Guidelines: Milk and Milk Products. Symposium on Milk, Hormones and Human Health, Harvard, Boston, Oct. 2006 www.milksymposium.ca.org
  • WHY 3 CUPS OF MILK?"“... the focus was, of course,the low calcium intake ofAmericans.”“... So in a world whereyou are tryingtoincrease calciumintake and simultaneouslyincrease potassium and, Carlos Camargo, MD, DrPHperhaps Vitamin D; milk Harvard University, Boston, MAlooks quite attractive.”Camargo C. 2005 US Dietary Guidelines: Milk and Milk Products. Symposium on Milk, Hormones and Human Health, Harvard, Boston, Oct. 2006 www.milksymposium.ca.org
  • MILK, CALCIUM & FRACTURES
  • Total n: 252,841 ü Prospective Studies do notshow association between Calcium intake & Hip fracture risk in Men and Women ü RCTs observe a slight increase in hip fracture risk with Ca monotherapy . .20 Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, et al. Am J Clin Nutr. 2007 Dec;86(6):1780-900
  • Bolland MJ, et al. BMJ. 2008 Feb 2;336(7638):262-6
  • MILK AND FRACTURES! No association in observational studies among adults RR/+1glass!Pooled analysis for categories of milk intake and hip fracture risk in womenfrom prospective cohort studies (6 studies, 195 102 women, 3574 fractures). " Bischoff-Ferrari HA et al. J Bone Mineral Res 2011; online Oct 2010, DOI 10.1002/jbmr.279"
  • MAJOR CONSTITUENT’S OF COW’S MILK"  ! Water! Fat! Protein! Lactose! Ash! Average! 86,6%! 4,1%! 3,6%! 5,0%! 0,7%! Chandan RC. Milk composition, physical and processing characteristics.In Hui YH, Chandan RC, Clark S, et al. Handbook of Food Products Manufacturing – Health, Meat, Milk, Poultry, Seafood, and Vegetables. John Wiley & Sons, 2007, pps 347-377
  • WHAT IS MILK?"Milk is a complex fluid,containing more than100,000 separate molecules,the levels of which vary withthe species! Chandan RC. Milk composition, physical and processing characteristics. In Hui YH, Chandan RC, Clark S, et al. Handbook of Food Products Manufacturing – Health, Meat, Milk, Poultry, Seafood, and Vegetables. John Wiley & Sons, 2007, pps 347-377
  • WHAT IS MILK?" !! !From a physiological standpoint, milk is:!! "“A unique biological secretion of the mammary gland endowed by nature to fulfil the entire nutritional needs of the neonate”." Chandan RC. Milk composition, physical and processing characteristics. In Hui YH, Chandan RC, Clark S, et al. Handbook of Food Products Manufacturing – Health, Meat, Milk, Poultry, Seafood, and Vegetables. John Wiley & Sons, 2007, pps 347-377
  • PURPOSE OF MILK Chandan RC. Milk composition, physical and processing characteristics.In Hui YH, Chandan RC, Clark S, et al. Handbook of Food Products Manufacturing – Health, Meat, Milk, Poultry, Seafood, and Vegetables. John Wiley & Sons, 2007, pps 347-377
  • HOW DOES MILK ACHIEVE THIS PURPOSE?
  • GI & INSULINLast AR, Wilson SA. Am Fam Physician 2006;73:1942-8
  • Gannon MC, Nuttall FQ, Krezowski PA, Billington CJ, Parker S. Diabetologia. 1986 Nov;29(11):784-91.
  • MILK’S INSULINOTROPIC RESPONSE Food" GI" II" Whole Milk" 30" 90" Fermented Milk" 15" 98" Lactose! 68! 50! Refined Wheat Bread! 100! 100! Ostman EM, et al. Am J Clin Nutr 2001;74:96 –100.
  • Milk (200 ml) + low GI CHOhas an insulin response ~ white bread Liljeberg Elmstahl H & Bjorck I. Eur J Clin Nutr 2001; 55:994–999.
  • WHOLE MILK VS SKIM MILK Glucose SKIM MILK WHOLE MILK Hoyt G et al. Br J Nutr. 2005 Feb;93(2):175-7
  • Consumption of milk induces a reactive hypoglycaemia similar to high glycaemic load carbohydratesOstman EM, et al. Am J Clin Nutr 2001;74:96 –100Hoyt G et al. Br J Nutr. 2005 Feb;93(2):175-7
  • IS THIS BENEFICIAL?
  • Whey ProteinsGLP-1 GIP Insulin Nilsson M, Holst JJ, Björck IM. Am J Clin Nutr. 2007 Apr;85(4):996-1004. Frid AH, Nilsson M, Holst JJ, Björck IM. Am J Clin Nutr. 2005 Jul;82(1):69-75.
  • Pratley RE, Gilbert M. Rev Diabet Stud. 2008 Summer;5(2):73-94
  • Insulin Hyperinsulinemia Resistance???Rizza RA, et al. Diabetologia. 1985 Feb;28(2):70-5Del Prato S, et al. Diabetologia. 1994 Oct;37(10):1025-35.Flores-Riveros JR, McLenithan JC, Ezaki O, Lane MD. Proc Natl Acad Sci 1993;90:512–6.
  • EPIDEMIOLOGY
  • Positive Studies Negative Studies •  Sahi T et al. Am J Clin Nutr. 1977;30:476-81•  Pereira MA et al. JAMA 2002;287:2081-9 •  Lau C et al. Diabetes Care. 2005 Jun;28(6):1397-403.•  Azadbakht L et al. Am J Clin Nutr. 2005 Sep;82(3):523-30 •  Lawlor DA et al. Diabet Med. 2005 Jun;22(6):808-11•  Liu S et al. Diabetes Care 2005;28: 2926-32. •  lmon R, et al. Eur J Nutr. 2010 Apr;49(3):141-6•  Elwood PC et al. J Epidemiol Community Health. 2007 Aug;61(8): 695-8. No association•  Hirschler V, et al. •  Ma B et al. J Pediatr. 2009 Jan;154(1):101-5 Am J Epidemiol. 2006 Sep 1;164(5):449-58. •  Snijder MB et al.•  Fumeron F, et al. Diabetes Care. 2011 Apr;34(4):813-7 Am J Clin Nutr. 2007 Apr;85(4):989-95
  • INTERVENTION STUDIES
  • ü  N= 24 boys (8 years old)ü  Consumed 53 g/d of Protein (1,5 lt of milk or 250 g meat) for 7 days Hoppe C, et al. Eur J Clin Nutr. 2005 Mar;59(3):393-8
  • %120,00100,00 80,00 60,00 MILK MILK 40,00 20,00 Meat Meat 0,00 Insulin HOMA Hoppe C, et al. Eur J Clin Nutr. 2005 Mar;59(3):393-8
  • Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen KF. Eur J Clin Nutr. 2009 Sep;63(9):1076-83
  • %   25   20   Whey   15   Casein   10   5   0   Insulin   HOMA   Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen KF. Eur J Clin Nutr. 2009 Sep;63(9):1076-83
  • on is shown in Fig. 1C (35). Using a GHRD subjects were E180/R43X heterozy ted mortality data for 53 additional To confirm IGF deficiency in this coh RESEARCH ARTICLE988 and obtained information on ill- IGF-2 concentrations (Fig. 1E) in 13 rela AGING unaffected first- to fourth-degree rel- ranging in Is Associated 20 to 50 years, inclu Growth Hormone Receptor Deficiency age from with a Major Reduction in Pro-Aging Signaling, GHRD cohort was identified on the in later used for in vitro studies. Serum IGF-1 Cancer, and Diabetes Humans (mean, 144 Jaime Guevara-Aguirre,1*† Priya Balasubramanian,2,3* Marco Guevara-Aguirre,1 Min Wei,3 Federica Madia,3 Chia-Wei Cheng,3 David Hwang,4 Alejandro Martin-Montalvo,5,6 ≤20 ng/ml Jannette Saavedra,1 Sue Ingles,7 Rafael de Cabo,5 Pinchas Cohen,4 Valter D. Longo2,3,8† 1E). Serum Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA dam- age in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead 735 ng/ml (m to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The in- Downloaded from stm.sciencemag.org on February 20, 2011 dividuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to but was bel a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum subjects (Fig from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular pro- tection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 mU/ml in the range versus 4.4 mU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher in- sulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a values betwe role of evolutionarily conserved pathways in the control of aging and disease burden in humans. INTRODUCTION tives (P < 0.0 of age-dependent mutations and neoplastic disease (20–23). Among The GHR Reduced activity of growth hormone (GH) and insulin-like growth the frequently detected mutations in human cancers are those that ac- factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman tivate two major signaling proteins downstream of the IGF-1 receptor organisms and the activation of stress resistance transcription factors (IGF-1R)—Ras and Akt—and those in the IGF-1R itself (24, 25). This ity from com and antioxidant enzymes contribute to extended life span and protec- is in agreement with a potential role for the IGF-1 signaling pathway in tion against age-dependent damage or diseases (1–16). Pathways that promoting age-dependent mutations that lead to the activation of regulate growth and metabolism also promote aging and genomic in- proto-oncogenes and for oncogenes in exacerbating the generation of (Fig. 1F) (41 stability, a correspondence that is conserved in simple eukaryotes and additional mutations and changes required for cancer progression (26). It mammals (7). In yeast, life span–extending mutations in genes such as has been proposed that the growth-promoting and antiapoptotic SCH9, the homolog of mammalian S6K (S6 kinase), protect against functions of the IGF-1 pathway underlie its putative role in cancer dered only age-dependent genomic instability (17–19). Similarly, mutations in development and progression (27). This link is supported by some the insulin/IGF-1–like signaling pathway increase life span Transl Med population studies but not others, which instead indicate a modest as- Guevara-Aguirre J, et al. Sci and reduce 2011, 3:1-9. abnormal cellular proliferation in worms, and mice deficient in GH sociation between high IGF-1 concentrations and increased risk of at least age 1 and IGF-1 are not only long-lived but also show delayed occurrence certain cancers (27, 28). GH may also promote insulin resistance. For example, age-dependent
  • observed no sign ing glucose conc RESEARCH ARTICLE (Fig. 2F). Howeve AGING centration in the Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, third of that in t Cancer, and Diabetes in Humans 0.05), and the H 1 † Jaime Guevara-Aguirre, * Priya Balasubramanian, * Marco Guevara-Aguirre, Min Wei, 3 3 Federica Madia, Chia-Wei Cheng, David Hwang, Alejandro Martin-Montalvo, 4 2,3 1 5,6 3 model assessmen 1 7 Jannette Saavedra, Sue Ingles, Rafael de Cabo, Pinchas Cohen, Valter D. Longo 5 4 2,3,8† (44) indicated that Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA dam- age in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored IR = 0.34) were m for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies. We combined this information with surveys than their relative to identify the cause and age of death for individuals in this community who died before this period. The in- 2H, P < 0.05). Th Downloaded from stm.sciencemag.org on February 20, 2011 dividuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum with the finding th from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular pro- GH-deficient m tection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 mU/ml versus 4.4 mU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulin serum insulin c resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher in- sulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans. insulin-sensitive Although GH INTRODUCTION of age-dependent mutations and neoplastic disease (20–23). Among cardiac dis vated Reduced activity of growth hormone (GH) and insulin-like growth the frequently detected mutations in human cancers are those that ac- the mortality from factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman tivate two major signaling proteins downstream of the IGF-1 receptor organisms and the activation of stress resistance transcription factors (IGF-1R)—Ras and Akt—and those in the IGF-1R itself (24, 25). This bining cardiac dis and antioxidant enzymes contribute to extended life span and protec- is in agreement with a potential role for the IGF-1 signaling pathway in tion against age-dependent damage or diseases (1–16). Pathways that promoting age-dependent mutations that lead to the activation of be similar to that regulate growth and metabolism also promote aging and genomic in- proto-oncogenes and for oncogenes in exacerbating the generation of stability, a correspondence that is conserved in simple eukaryotes and additional mutations and changes required for cancer progression (26). It mammals (7). In yeast, life span–extending mutations in genes such as has been proposed that the growth-promoting and antiapoptotic SCH9, the homolog of mammalian S6K (S6 kinase), protect against functions of the IGF-1 pathway underlie its putative roledeaths in relative in cancer age-dependent genomic instability (17–19). Similarly, mutations in development and progression (27). This link is supported by some GHRD subjects) ( the insulin/IGF-1–like signaling pathway increase life span and reduce population studies but not others, which instead indicate a modest as- abnormal cellular proliferation in worms, and mice deficient in GH sociation between high IGF-1 concentrations and increased risk ofnd mortality in the Ecuadorian cohort.long-lived but also J, et delayed occurrence certain unaffected resistance. For example, age-dependent of a huma and IGF-1 are not only Guevara-Aguirre show al.of Transl Med 2011,cancers (27, 28). (A) Causes Sci death in may also promote insulin relatives studies GH 3:1-9. s. (B) Percentage of cancers per age group in unaffected (29–32), andisGH replacement andGHRD (GHR)–deficient 1 mice relatives andtherapy can exacerbate insulin re- insulin resistance reduced in GH- GH receptor Institute of Endocrinology, Metabolism and Reproduction, Quito, Ecuador. 2Depart-
  • RESEARCH ARTICLEAGINGGrowth Hormone Receptor Deficiency Is Associatedwith a Major Reduction in Pro-Aging Signaling,Cancer, and Diabetes in HumansJaime Guevara-Aguirre,1*† Priya Balasubramanian,2,3* Marco Guevara-Aguirre,1 Min Wei,3Federica Madia,3 Chia-Wei Cheng,3 David Hwang,4 Alejandro Martin-Montalvo,5,6Jannette Saavedra,1 Sue Ingles,7 Rafael de Cabo,5 Pinchas Cohen,4 Valter D. Longo2,3,8†Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA dam-age in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitoredfor 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that leadto severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies. We combined this information with surveysto identify the cause and age of death for individuals in this community who died before this period. The in- Downloaded from stm.sciencemag.org on February 20, 2011dividuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast toa prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very lowincidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNAbreaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serumfrom GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target ofrapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular pro-tection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 mU/mlversus 4.4 mU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulinresistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher in-sulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for arole of evolutionarily conserved pathways in the control of aging and disease burden in humans. 0    INTRODUCTION Cases   of age-dependent mutations and neoplastic disease (20–23). AmongReduced activity of growth hormone (GH) and insulin-like growth the frequently detected mutations in human cancers are those that ac-factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman tivate two major signaling proteins downstream of the IGF-1 receptororganisms and the activation of stress resistance transcription factors (IGF-1R)—Ras and Akt—and those in the IGF-1R itself (24, 25). Thisand antioxidant enzymes contribute to extended life span and protec- is in agreement with a potential role for the IGF-1 signaling pathway intion against age-dependent damage or diseases (1–16). Pathways that promoting age-dependent mutations that lead to the activation ofregulate growth and metabolism also promote aging and genomic in- proto-oncogenes and for oncogenes in exacerbating the generation ofstability, a correspondence that is conserved in simple eukaryotes and additional mutations and changes required for cancer progression (26). Itmammals (7). In yeast, life span–extending mutations in genes such as has been proposed that the growth-promoting and antiapoptoticSCH9, the homolog of mammalian S6K (S6 kinase), protect against functions of the IGF-1 pathway underlie its putative role in cancerage-dependent genomic instability (17–19). Similarly, mutations in development and progression (27). This link is supported by somethe insulin/IGF-1–like signaling pathway increase life span and reduce population studies but not others, which instead indicate a modest as- Guevara-Aguirre J, et al. Sci Transl Med 2011, 3:1-9.abnormal cellular proliferation in worms, and mice deficient in GH sociation between high IGF-1 concentrations and increased risk ofand IGF-1 are not only long-lived but also show delayed occurrence certain cancers (27, 28). GH may also promote insulin resistance. For example, age-dependent
  • July 2011 GLP-1–BASED THEElashoff M, et al. Gastroenterology. 2011 Jul;141(1):150-6. sitagliptin) was reported for t analysis. Discussion We report a 6-fold i event rate for pancreatitis wi GLP-1 based drugs available o States, exenatide and sitaglipt FDA AERS database. Analysis of the FDA AERS mechanism to compare adverse Limitations of the FDA AERS d plete data and reporting biase ever, AERS has proven effectiv tions at detecting unintended analysis was undertaken notw tions, given the paucity of saf class of drugs, which is gainin for a common disease. Rando Figure 1. Odds ratio of test vs control events for exenatide, sitagliptin, trials remain the gold stand
  • HORMONES IN MILK
  • MILK & IGFS
  • DOES IT MATTER???
  • Published assays relate exclusively tothe IGF-I content in the whey fraction of milk" !! Underestimate the total IGF-I content in milk" Gauthier SF, Pouliot Y, Maubois JL. Lait 2006; 86: 99-125. Baumrucker CR, Erondu NE. J Mammary Gland Biol Neoplasia 2000; 5: 53-64. Collier RJ, Miller MA, Hildebrandt JR, et al. J Dairy Sci 1991; 74:2905-2911.
  • 16  14   Whey  12  10   Casein   8   6   4   2   0   IGF-­‐1   IGF-­‐1  /  IGBP-­‐3   Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen KF. Eur J Clin Nutr. 2009 Sep;63(9):1076-83
  • CASEIN PER LITERGrs252015 COW’S MILK10 5 HUMAN MILK 0 Park YW, Haenlein GFW. Handbook of milk of non-bovine mammals. Blackwell Publishing, 2006
  • •  Casein and, to a lesser degree, BSA & Lactoferrin prevent IGF-1 Proteolysis in ratsXian CJ, Shoubridge CA, Read LC. J Endocrinol. 1995 Aug;146(2):215-25.
  • RBGH INCREASES MILK IGF-1""" Faulkner A. J Dairy Res. 1999 May;66(2):207-14.
  • Mastitis increases IGF-1 concentrations in Milk"Sheffield LG. J Dairy Sci 1997; 80: 2020-2024.Liebe A, Schams D. J Dairy Res 1998; 65: 93-100.Bruckmaier RM, Ontsouka CE, Blum JW. Vet Med-Czech 2004; 49: 283-290.Shuster DE, Kehrli ME, Baumrucker CR. Proc Soc Exp Biol Med 1995; 210:140–149.
  • MILK INCREASES IGF-1 IN HUMANS Estudo de intervenção N= 82 moças caucasianas com 12 anos Duração: 18 meses 20-30% increase in Children Hoppe C, Mølgaard C, Michaelsen KF. Annu Rev Nutr. 2006;26:131-73. Rogers IS, et al. Cancer Epidemiol Biomarkers Prev 2005; 14: 204-212. Hoppe C, et al. Am J Clin Nutr 2004; 80: 447-452. Hoppe C, et al. Eur J Clin Nutr 2004; 58: 1211-1216.
  • MILK INCREASES IGF-1 IN HUMANS Estudo de intervenção N= 82 moças caucasianas com 12 anos Duração: 18 meses 10-20% Increase in AdultsNorat T, et al. Eur J Clin Nutr 2007; 61: 91-98.Ma J, et al. J Natl Cancer Inst 2001, 93:1330-1336.Morimoto LM, et al. Cancro Causes Control 2005; 16: 917-927.Giovannucci E, et al. Cancer Epidemiol Biomarkers Prev 2003, 12:84-89Holmes MD, et al. Cancer Epidemiol Biomarkers Prev 2002; 11: 852-861.
  • MILK INCREASES IGF-1/IGFBP-3 IN HUMANS Estudo de intervenção N= 82 moçasRich-Edwards JW, Ganmaa D, Pollak MN, et al. Milk consumption and the caucasianas com 12 anosprepubertal somatotropic axis. Nutr J. 2007 Sep 27;6:28. Hoppe C, Molgaard C, Juul A, et al. High intakes of skimmed milk, but not Duração: 18 meses meat, increase serum IGF-I and IGFBP-3 in eight-year-old boys. Eur J Clin Nutr. 2004 Sep;58(9):1211-6Gunnell D, Oliver SE, Peters TJ, et al. Are diet prostate cancerassociations mediated by the IGF axis?. A cross-sectionalanalysis of diet, IGF-I and IGFBP-3 in healthy middle-agedmen. Br. J Cancer 2003; 88: 1682-1686.
  • 16  14   Whey  12  10   Casein   8   6   4   2   0   IGF-­‐1   IGF-­‐1  /  IGBP-­‐3   Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen KF. Eur J Clin Nutr. 2009 Sep;63(9):1076-83
  • ü Standard Method: 71,7ºC for 15’’" ü UHT: " 130º-150ºC for 1-5’’ " UHT 130º for 2’’ reduces IGF-1 by 10%Thomas EL. J Dairy Sci 1981; 64: 1023-1027.Elliott AJ, et al. J Dairy Res 2005; 72: 442–446.Kang SH, et al. J Dairy Sci 2006; 89: 402-409.
  • PASTEURIZATION"121ºC for 15 min reduces IGF-1 to virtually undetected levels Collier RJ, et al. J Dairy Sci 1991; 74:2905-2911
  • PASTEURIZATION" Yogurt: " ü 85ºC for 30 min" ü 95ºC for 10 min" " http://www.milkfacts.info/Milk%20Processing/Milk%20Processing%20Page.htm75º for 15 min decreases IGF-1 by 45% Kang SH, et al. J Dairy Sci 2006; 89: 402-409.
  • FERMENTATION" !! !!! !! !! !!" """ "Reduces IGF-1 (measured in whey) by 20%" "" " " ! Kang SH, et al. J Dairy Sci 2006; 89: 402-409.
  • Melnik BC, Schmitz G. Exp Dermatol. 2009 Oct;18(10):833-41
  • Wilkinson SB, et al. Am J Clin Nutr. 2007 Apr;85(4):1031-40
  • Elevated plasmaIGF-1/ IGFBP-3 ratiorepresents a risk factor forcertain epithelial cellcancers" Cordain L. et al. Comparative Biochemistry and Physiology Part A 2003; 136: 95–112
  • Oncogene (2009), 1–13 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/oncREVIEWEmerging role of insulin-like growth factor receptor inhibitors in oncology:early clinical trial results and future directionsA Gualberto1,2 and M Pollak31Clinical Department, Pfizer Oncology, New London, CT, USA; 2Department of Pathology, Brown University Alpert School ofMedicine, Providence, RI, USA and 3Department of Oncology, McGill University, Montreal, Quebec, CanadaPreclinical evidence that targeting the insulin-like growth alterations that reduce ligand levels (Pollak et al., 2001,factor receptor (IGF-IR) is effective in cancer treatment 2004; Baserga et al., 2003; Majeed et al., 2005; Hartoghas been accumulating for almost two decades. Efforts to et al., 2007; Sachdev and Yee, 2007; Samani et al., 2007;develop drugs began in the late 1990s, and initial data Chitnis et al., 2008; Weroha and Haluska, 2008; Yuenfrom clinical trials were reported in 2006. The biological and Macaulay, 2008; Pollak, 2008a) as well as knock-rationale for IGF-IR targeting has potential relevance down methods (Wu et al., 2003). One important themeto many tumor types, and early results have justified that emerged from this work was the notion thatexpanded programs to evaluate IGF-IR-targeting agents multiple oncogenes require the presence of the insulin-in many areas of clinical need. More than two dozen drug like growth factor receptor (IGF-IR) to achieve cellularcandidates have been developed and clinical trials are transformation (Sell et al., 1993; Martin et al., 2006);underway for at least 12 of these. Early clinical trials another was that that IGF-I signaling confers resistancereveal an acceptable safety profile together with pharma- to many antineoplastic therapies (Wiseman et al., 1993;codynamic evidence that the receptor can be successfully Lu et al., 2001). Interest in IGF-IR targeting increased
  • Archives of Physiology and Biochemistry, 2009; 115(2): 58–71 REVIEW ARTICLE e insulin-like growth factor-I receptor as an oncogene Haim Werner1, and Ilan Bruchim2 1 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, and 2Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba 44281, a liated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Abstract The insulin-like growth factor-I receptor (IGF-IR) mediates the biological actions of both IGF-I and IGF-II. The IGF-IR is expressed in most transformed cells, where it displays potent antiapoptotic, cell-survival, and transforming activities. IGF-IR expression is a fundamental prerequisite for the acquisition of a malignant phenotype, as suggested by the nding that IGF-IR-null cells (derived from IGF-IR knock-out embryos) are unable to undergo transformation when exposed to cellular or viral oncogenes. This review article will focus on the underlying molecular mechanisms that are responsible for the normal, physiological control of IGF-IR gene expression, as well as the cellular pathways that underlie its aberrant expression in cancer. Examples from the clinics will be presented, including a description of how the IGF system is involved in14 May 2009 breast, prostate, pediatric, and gynecological cancers. Finally, current attempts to target the IGF-IR as a therapeutic approach will be described. Keywords: Insulin-like growth factor-I (IGF-I); IGF-I receptor; targeted therapies; gene expression; cancer
  • RESEARCH ARTICLE AGING Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans Jaime Guevara-Aguirre,1*† Priya Balasubramanian,2,3* Marco Guevara-Aguirre,1 Min Wei,3 Federica Madia,3 Chia-Wei Cheng,3 David Hwang,4 Alejandro Martin-Montalvo,5,6 Jannette Saavedra,1 Sue Ingles,7 Rafael de Cabo,5 Pinchas Cohen,4 Valter D. Longo2,3,8† Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA dam- age in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The in- Downloaded from stm.sciencemag.org on February 20, 2011 dividuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular pro- tection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 mU/ml versus 4.4 mU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher in- sulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans. INTRODUCTION of age-dependent mutations and neoplastic disease (20–23). Among Reduced activity of growth hormone (GH) and insulin-like growth the frequently detected mutations in human cancers are those that ac- factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman tivate two major signaling proteins downstream of the IGF-1 receptor organisms and the activation of stress resistance transcription factors (IGF-1R)—Ras and Akt—and those in the IGF-1R itself (24, 25). This and antioxidant enzymes contribute to extended life span and protec- is in agreement with a potential role for the IGF-1 signaling pathway in tion against age-dependent damage or diseases (1–16). Pathways that promoting age-dependent mutations that lead to the activation of regulate growth and metabolism also promote aging and genomic in- proto-oncogenes and for oncogenes in exacerbating the generation of stability, a correspondence that is conserved in simple eukaryotes and additional mutations and changes required for cancer progression (26). It mammals (7). In yeast, life span–extending mutations in genes such as has been proposed that the growth-promoting and antiapoptotic SCH9, the homolog of mammalian S6K (S6 kinase), protect against functions of the IGF-1 pathway underlie its putative role in cancer age-dependent genomic instability (17–19). Similarly, mutations in development and progression (27). This link is supported by some the insulin/IGF-1–like signaling pathway increase life span and reduce population studies but not others, which instead indicate a modest as- abnormal cellular proliferation in worms, and mice deficient in GH sociation between high IGF-1 concentrations and increased risk of and IGF-1 are not only long-lived but also show delayed occurrence certain cancers (27, 28). Guevara-Aguirre J, et al. Sci Transl Med 2011,may also promote insulin resistance. For example, age-dependent GH 3:1-9.Fig. 1. Ecuadorian cohort. (A and B) Several members of the GHRD co 1 Institute of Endocrinology, Metabolism and Reproduction, Quito, Ecuador. 2Depart- insulin resistance is reduced in GH- and GH receptor (GHR)–deficient mice (29–32), and GH replacement therapy can exacerbate insulin re- ment of Molecular and Computational Biology, University of Southern California, Los
  • RESEARCH ARTICLEAGINGGrowth Hormone Receptor Deficiency Is Associatedwith a Major Reduction in Pro-Aging Signaling,Cancer, and Diabetes in HumansJaime Guevara-Aguirre,1*† Priya Balasubramanian,2,3* Marco Guevara-Aguirre,1 Min Wei,3Federica Madia,3 Chia-Wei Cheng,3 David Hwang,4 Alejandro Martin-Montalvo,5,6Jannette Saavedra,1 Sue Ingles,7 Rafael de Cabo,5 Pinchas Cohen,4 Valter D. Longo2,3,8†Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA dam-age in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitoredfor 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that leadto severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies. We combined this information with surveysto identify the cause and age of death for individuals in this community who died before this period. The in- Downloaded from stm.sciencemag.org on February 20, 2011dividuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast toa prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very lowincidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNAbreaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serumfrom GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target ofrapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular pro-tection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 mU/mlversus 4.4 mU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulinresistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher in-sulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a 1     0    role of evolutionarily conserved pathways in the control of aging and disease burden in humans. Case   Cases  INTRODUCTION of age-dependent mutations and neoplastic disease (20–23). AmongReduced activity of growth hormone (GH) and insulin-like growth the frequently detected mutations in human cancers are those that ac-factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman tivate two major signaling proteins downstream of the IGF-1 receptororganisms and the activation of stress resistance transcription factors (IGF-1R)—Ras and Akt—and those in the IGF-1R itself (24, 25). Thisand antioxidant enzymes contribute to extended life span and protec- is in agreement with a potential role for the IGF-1 signaling pathway intion against age-dependent damage or diseases (1–16). Pathways that promoting age-dependent mutations that lead to the activation ofregulate growth and metabolism also promote aging and genomic in- proto-oncogenes and for oncogenes in exacerbating the generation ofstability, a correspondence that is conserved in simple eukaryotes and additional mutations and changes required for cancer progression (26). Itmammals (7). In yeast, life span–extending mutations in genes such as has been proposed that the growth-promoting and antiapoptoticSCH9, the homolog of mammalian S6K (S6 kinase), protect against functions of the IGF-1 pathway underlie its putative role in cancerage-dependent genomic instability (17–19). Similarly, mutations in development and progression (27). This link is supported by somethe insulin/IGF-1–like signaling pathway increase life span and reduce population studies but not others, which instead indicate a modest as-abnormal cellular proliferation in worms, and mice deficient in GH sociation between high IGF-1 concentrations and increased risk ofand IGF-1 are not only long-lived but also J, et delayed occurrence certain cancers (27, 28). Guevara-Aguirre show al. Sci Transl Med 2011, 3:1-9. GH may also promote insulin resistance. For example, age-dependent insulin resistance is reduced in GH- and GH receptor (GHR)–deficient1 Institute of Endocrinology, Metabolism and Reproduction, Quito, Ecuador. 2Depart- mice (29–32), and GH replacement therapy can exacerbate insulin re-
  • European Journal of Endocrinology (2011) 164 485–489 ISSN 0804–4643 CLINICAL STUDY Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies Rachel Steuerman1, Orit Shevah1 and Zvi Laron1,2 1 Endocrinology and Diabetes Research Unit, Schneider Children’s Medical Center, 14 Kaplan Street, Petah Tikva 49202, Israel and 2WHO Collaborating Center for the Study of Diabetes in Youth, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (Correspondence should be addressed to Z Laron at Endocrinology and Diabetes Research Unit, Schneider Children’s Medical Center; Email: laronz@clalit.org.il) LS – secondary congenital deficiency of IGF1 and primary GH insensitivity, due to defects in the GH receptor. cIGHD – Primary congenital isolated hGH deficiency EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164 GH/IGF1 deficiency and cancer 487 Abstract GHRHReceptor (R) defect – secondary hGH deficiency. Objective: To investigate whether congenital IGF1 deficiency confers protection against development of Table 2 The prevalence of malignancy in the four diagnostic the prevalence of malignancies in patients with hormone(secondary) malignancies, by comparing groups. Congenital multiple pituitary congenital deficiency, including hGH cMPHD – deficiency of IGF1 with the prevalence of cancer in their family members. Method: Only patients with an ascertained Diagnostic groups syndrome (LS), congenital IGHD, diagnosis of either LaronPrevalence of malignancy in the congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect werefour diagnostic groups included Laronstudy. In addition tocIGHD patients, we GHRHR a worldwide survey and collected in this sydrome our own performed defects cMPHD data on a total of 538 patients, 752 of their first-degree family members, of which 274 were siblings Total and 131 were further family members. Patients Results: We found that none of the 230 LS patients developed cancer and that only 1 out of 116 Total number (n) 230 116 79 113 patients with congenital IGHD, also suffering from xeroderma pigmentosum, had a malignancy. Out of 538 Number of malignancies 0 with GHRHR defects and out of 113 patientsc with congenital MPHD,3we found three 79 patients 1b 3 d 7 Prevalence of malignancy (%) patients with cancer in each group.0.9 0.0 3.8 2.7 1.3 First-degree relatives Among the first-degree family members (most heterozygotes) of LS, IGHD and MPHD, we found Total number (n) 30 cases218cancer and 1 suspected. In addition, 31 150 of 203 malignancies were reported among 131 181 752 further relatives. Number of malignancies 18 (15) 7 (6) 0 5C1a (6) 30 (26C1)a Conclusions: Our findings bear heavily on the relationship between GH/IGF1 and cancer. Homozygous Prevalence of malignancy (%) 8.3 3.4 0.0 2.8 patients with congenital IGF1 deficiency and insensitivity to GH such as LS seem protected from future 4.0 Further relatives cancer development, even if treated by IGF1. Patients with congenital IGHD also seem protected. Total number (n) 113 13 4 1 131 Number of malignancies European 25 (24) Endocrinology 164 (4) Journal of 4 485–489 1 (1) 1 (1) 31 (30) Prevalence of malignancy (%) 22.1 30.8 25 – 23.7 Siblings only Introduction whereas 24% of their heterozygous family members Total number (n) 86 96 had (13). We 6 also showed that 35 86patients with 274 Number of malignancies their proliferative, differentiation and apoptotic (2) Linked to 5 (4) 2 congenital (c) IGHD and 18 with GHRH(2) 0 2 receptor (R) 9 (80) Prevalence of malignancy both GH and insulin-like growth factor 1 mutation reported no malignancies. In2.3 properties, (%) 5.8 2.1 0.0 contradiction, 3.3 P values (IGF1) have been identified as risk factors for certain 9–24% of their family members had a history of cancer. Patients versus first-degree relatives in the!0.001 age group and malignancies (1–5), even pediatric 0.43 The aim of the present study was 1 extend our 0.04 to 0.019 Patients versus furtheradults (6–8). There is also evidence that most findings by enlarging the number of patients with LS young relatives !0.001 !0.001 0.182 – !0.001 Patients versus siblingsand transformed cells 0.005 increased IGF1 and cIGHD and to collect data on patients with GHRHR tumors display 0.59 1 1 !0.165 receptor (IGF-1R) concentration and high IGF1R mRNA, mutations and congenital multiple pituitary hormone causing enhanced IGF1 binding (9, 10), leading to the deficiency (cMPHD), including GH. Number in parentheses indicate number of individuals. aIndicates one suspected malignancy; bincludes one male basal cell carcinoma diagnosed at 15 years; c axiom that overexpression of IGF1R is a pre-requirement d
  • BETA-CELLULIN
  • BETA-CELLULIN IN DAIRYBastian SE, et al. Measurement of betacellulin levels in bovine serum, colostrum and milk. J Endocrinol. 2001 Jan;168(1):203-12.
  • TGF-α: Transforming Growth Factor Alpha HB-EGF: Heparin Binding EGF EPR: Epiregulin AR: Amphiregulin (NRG1, NRG2, NRG3, NRG4): Neuregulins 1, 2, 3 and 4 ErB1 – EGF-R Cordain L. Dietary implications for the development of acne: a shifting paradigm.In: U.S. Dermatology Review II 2006, (Ed.,Bedlow, J). Touch Briefings Publications, London, 2006.
  • EGF in saliva: 0.0512 ng/ mlTotal Saliva Secretion: 691 ml/24 hoursEGF in 24 hour Saliva: 35.3 ng BTC per liter of Bovine Milk: 1930 ng Cordain L. Dietary implications for the development of acne: a shifting paradigm. In: U.S. Dermatology Review II 2006, (Ed.,Bedlow, J). Touch Briefings Publications, London, 2006.
  • EGF upregulates its own receptor Increased signalling Cordain L. U.S. Dermatology Review II 2006, (Ed.,Bedlow, J). Touch Briefings Publications, London, 2006
  • EGF-R OVEREXPRESSION OCURS IN VARIOUS TYPES OF CANCER ü Breast ü  Pancreas ü Colon ü  Stomach ü Prostate ü  Testicle ü Ovaries ü  Kidney ü Lung ü  Head & NeckNanda R. Rev Recent Clin Trials. 2007 May;2(2):111-6. Cohen D, et al. Clin Genitourin Cancer. 2007 Mar;5(4):264-70.Gravis G, Bladou F, Salem N, et al. Ann Oncol. 2008 May 7. Davies DE, Chamberlin SG. Biochem Pharmacol. 1996 May 3;51(9):1101-10.Palayekar MJ, Herzog TJ. Int J Gynecol Cancer. 2007 Dec 5. Seiwert TY, Cohen E. Angiogenesis Oncol 2005;1:7-10Mándoky L, et al. Anticancer Res. 2004 Jul-Aug;24(4):2219-24. Henson ES, Gibson SB. Cell Signal. 2006 Dec;18(12):2089-97.
  • SOME EFFECTS OF BETA- CELLULIN & IGF-1
  • Milk e aumento da estatura
  • MILK INCREASES LINEAR GROWTHEpidemiological StudiesHoppe et al. Am J Clin Nutr 2004;80:447-52Paganus et al. Acta Paediatr 1992;81:518-21Stallings et al. JPGN 1994;18:440-5Isolauri et al. J Pediatr 1998;132:1004-9Black et al. Am J Clin Nutr 2002;76:675-80
  • information was not provided, it is not possible to evaluate the degree to which theAnnu. Rev. Nutr. 2006.26:131-173. Downloaded from www.annualreby Lund University Libraries, Head Office on 07/25/11. For personal children participating in the study were poorly nourished at the onset of the study. However, because this study was conducted in the 1920s, it is plausible that some degree of malnutrition was present. More remarkable results than those of the Boyd Orr study were found with a similar supplementation program in New Guinea. It was conducted among 7- to 13-year-old Bundi children who had a very-low-protein diet and the majority of Height increase Boyd Orr Study (1928) 1.6 1.4 1.2 1 Inches 0.8 0.6 0.4 0.2 0 6 y group 9 y group 13 y group whole milk skimmed milk biscuits control Annu. Rev. Nutr. 2006. 26:131–73 Figure 4 Height increases during a seven-month period in the classical Boyd Orr study
  • Nilo,c   Country   Height   Pastoralists   Dinka1   Sudan   181.9  cm   Shilluk1   Sudan   182.6  cm   Tanzania   Maasai2   &  Kenya   173.5  cm  1 - Roberts DF, Bainbridge DR. Am J Phys Anthropol 1963; 21 (3): 341–3702 - Mann GV. Am J Clin Nutr. 1974 May;27(5):464-9
  • Green J. Lancet Oncol. 2011 Jul 20
  • Milk promotes linear growth & may promote Premature Puberty Wiley AS. Cow’s Milk Consumption and Health – An Evolutionary Perspective. In Trevathan WR, Smith EO, McKenna JJ. Evolutionary Medicine and Health – New Perspectives. Oxford University Press, 2008.
  • Increased insulin/IGF-1 signaling reduces nuclear levels of FoxO1, the key regulator in acne pathogenesis! Insulin IGF-1 Melnik BC. Br J Dermatol. 2010 Jun;162(6):1398-400. Melnik BC. J Dtsch Dermatol Ges. 2010 Feb;8(2):105-14. P P PI3K Akt P 14-3-3 protein P P P FoxO1 FoxO1 Akt P ProteasomeLow nuclear P  AR  level of FoxO1 FoxO1Androgen receptor Keratinocyte Increased seba- Inflammationtransactivation proliferation ceous lipogenesis NFκB upregulation
  • ESTROGENS IN MILK"Farlow DW, Xu X, Veenstra TD. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 May 1;877(13):1327-34
  • ESTRONE SULFATE (WHEY)pg/ml Sulfato de Estrona no lactosoro1000 900 800 700 600 500 400 300 200 100 Controlo 0 Vaca no Non Pregnant Vaca Embarazada Pregnant Cow! Vaca Embarazada Pregnant Cow! embarazada Cow! (41-60 dias) (41-60 days)! (220-240 dias) (220-240 days)! Sato A. Health Effects of Cow Milk. Symposium on Milk, Hormones and Human Health, Harvard, Boston, Oct. 2006 www.milksymposium.ca.org
  • ESTROGENS IN MILKFarlow DW, Xu X, Veenstra TD. J Chromatogr B 2009 May 1;877(13):1327-34
  • ESTROGENS IN MILK Highly Reactive Catechol EstrogensFarlow DW, Xu X, Veenstra TD. J Chromatogr B 2009 May 1;877(13):1327-34
  • DOES IT MATTER???
  • Commercial milk isuterotrophic in rats Ganmaa D, Tezuka H, Enkhmaa D, et al. Int J Cancer 2006; 118: 2363-2365. Ganmaa D, Sato A. Med Hypotheses 2005; 65: 1028-37.
  • Commercial whole, low, and nonfat milk promote growth of! DMBA-induced mammary tumors in rats.!DMBA = 7,12-dimethylbenz(a) anthracene Qin LQ, Xu JY, Wang PY, et al. Int J Cancer 2004; 110: 491-496. Qin LQ, Xu JY, Tezuka H, et al. Cancer Detect Prev 2007; 31: 339-343. Ma DF, Katoh R, Zhou H, et al. Acta Histochem Cytochem 2007; 40: 61-67. Zhou H, Qin LQ, Tang FL, et al. Food Chem Toxicol 2007; 45: 1868-1872.
  • a rich source of estrogens. Indeed, E2 concentration is high mammary drainage than in the peripheral circulation in h men yielding cows.12 Pregnant cows are under the control of relatour out of five women, ovulation occurred during milk intake high levels of estrogens, and milk produced from pregnant che second menstrual cycle, and the timing of ovulation was contains correspondingly high concentrations of estrogilar among the three menstrual cycles. In these four women, Estrogen concentration in milk has been measured sincethird menstruation and ovulation occurred regularly. In one 1970s, mainly as an indicator of pregnancy.15,16 Concentratioman, however, aged 36 years who had a menstrual cycle of E1 sulfate increases from 30 pg/mL in non-pregnant cow (a) (b) (c) (d) 140 P<0.02 140 P<0.02 140 P<0.02 7 P<0.02 120 120 120 6 100 100 100 5 (µg/h) (ng/h) (ng/h) (ng/h) 80 80 80 4 60 60 60 3 40 40 40 2 20 20 20 1 Basal Peak Basal Peak Basal Peak Basal Peak. 5 Comparison between basal excretion volumes (basal) and maximum excretion volumes (peak) of (a) urine estrone, (b) estradio Comparison between basal intake of volumes in prepubertal children (n = 6).iol and (d) pregnanediol before and after excretion cow milk (basal) and maximum excretion volumes (peak) of (a) urine estrone, (b) estradiol, (c) estriol and (d) pregnanediol before and after intake of cow milk in prepubertal children (n = 6).2010 Japan Pediatric Society
  • E2 PRODUCTION RATE VS EXCRETION INng PREPUBERTAL BOYS120   Maruyama K, Oshima T, Ohyama K. Pediatr Int. 2010 Feb;52(1):33-8.100   80   60   40   20   0   E2 Production rate Net increase of E2 excretion ng/day ng/4h
  • (a) (b) (c) (a) P<0.02 NS P<0.02 150 40 0.8 4 30 0.6(ng/mL) 3 (pg/mL) (ng/mL) (mIU/mL) 100 20 0.4 2 50 10 0.2 1 Basal Peak Basal Peak Basal PeakFig. 1 Comparison between basal levels and peak levels of (a)serum estrone (E1), (b) estradiol (E2) and (c) progesterone before Fig. 2and after intake of cow milk in men (n = 7). luteini ostero Maruyama K, Oshima T, Ohyama K. Pediatr Int. 2010 Feb;52(1):33-8.
  • e before and after milk intake are shown in Figure 2. Changes in urinary excretion volumes of E1, E2, E3 aLH and FSH concentration gradually decreased in six out nanediol are shown in Figure 4. Urinary excretion patten men, and reached a nadir 60–120 min after the intake of similar among these four hormones. Peak excretion v (a) (b) (c) (d) 1000 300 P<0.02 P<0.02 P<0.02 P<0.02 900 250 120 20 100 800 200 (ng/h) 15 (ng/h) 80 (mg/h) (ng/h) 700 150 60 10 600 100 40 5 500 50 20 Basal Peak Basal Peak Basal Peak Basal PeakComparison between basal between basal excretionand maximum excretion volumes (peak) of (a) urine estrone, (b) estr Comparison excretion volumes (basal) volumes (basal) and maximum excretion volumesnd (d) pregnanediol before urine estrone, (b) cow milk in men (n = and (d) pregnanediol before and after (peak) of (a) and after intake of estradiol, (c) estriol 7). intake of cow milk in men (n = 7). © 2010 Japan Pediatri Maruyama K, Oshima T, Ohyama K. Pediatr Int. 2010 Feb;52(1):33-8.
  • (a) (b) (c) P<0.05 P<0.02 P<0.02 4 4 8 3 3 6 (mIU/mL) (mIU/mL) (ng/mL) 2 2 4 1 1 2Peak Basal Nadir Basal Nadir Basal Nadirof (a) Comparison between basal and nadir levels of (a) serum luteinizing hormone, (b)before Fig. 2 Comparison between testosterone before and after intake of cow follicle-stimulating hormone and (c) basal and nadir levels of (a) serum luteinizing hormone, (b) milk in men (n = 7). follicle-stimulating hormone and (c) test- osterone before and after intake of cow milk in men (n = 7). Maruyama K, Oshima T, Ohyama K. Pediatr Int. 2010 Feb;52(1):33-8.ations
  • Estrogens are implicated in Prostate, Ovarian, Uterine & Breast cancer1.  Schairer C, Hill D, Sturgeon SR et al. Cancer Epidemiol Biomarkers Prev 2005; 14: 1660-1665.2.  Hankinson SE, Eliassen AH. J Steroid Biochem Mol Biol 2007; 106: 24-30.3.  Eliassen AH, Missmer SA, Tworoger SS, et al. J Nat Cancer Inst 2006; 98: 1406-1415.4.  Cavalieri E, Chakravarti D, Guttenplan J, et al. Biochim Biophys Acta 2006; 1766: 63-78.5.  Persson I. J Steroid Biochem Mol Biol 2000;74:357–64.6.  Yager JD, Davidson NE. N Engl J Med 2006; 354: 270-82.7.  Ganmaa D, Sato A. Med Hypotheses 2005; 65: 1028-378.  Qin LQ, Wang PY, Kaneko T, et al. Med Hypotheses. 2004;62(1):133-42.9.  Shantakumar S, Terry MB, Paykin A, et al. Am J Epidemiol. 2007;165: 1187-1198.10.  Kahlenborn C. Modugno F, Potter DM, et al. Mayo Clin Proc. 2006;81: 1290-1302.11.  Chlebowski RT, Hendrix SL, Langer RD, et al. JAMA. 2003 Jun 25;289(24):3243-53.12.  Rossouw JE, Anderson GL, Prentice RL, et al. JAMA. 2002 Jul 17;288(3):321-33 .13.  Beral V; Million Women Study Collaborators. Lancet. 2003 Aug 9;362(9382):419-27.14.  Chen WY, Manson JE, Hankinson SE, et al. Arch Intern Med 2006; 166: 1027-1032.
  • DHT PRECURSORS IN MILK
  • Milk Milk 1.  BPH 2.  Acne 3.  Male Pattern Baldness Milk DHTDanby FW. Clinics in Dermatology 2010; 28: 598–604
  • ARE COWS ON A QUEST FOR REVENGE?? "
  • CANCER & MILKEpidemiology
  • PROSTATE CANCER
  • products, butter (0.85–2.09) energydt et al. (23)b United States 69/385 Hospital 3 Milk 1.26 Age, energy (0.57–2.79) META-ANALYSIS SCHEMATIC CONCERNING THE OR OF PROSTATE CANCEROR and CI compared the highest with the lowest quantile of consumption and reflected the greatest degree of control for confounders. They were th rom the first food itemASSOCIATED WITH MILK CONSUMPTION IN 11 CASE-CONTROL STUDIES in the Items column.Studies included in the calculation of meta-analysis. Horizontal bars represent the 95% CI.OR and 95% CI were calculated from the numbers of cases and controls using a standard method. The combined OR in the random-effects model was 1.68 (CI = 1.34–2.12). Qin LQ, et al. Nutr Cancer. 2004;48(1):22-7re 1. Meta-analysis schematic concerning the OR of prostate cancer associated with milk consumption in 11 case-control studies calculateat™ software (7). Horizontal bars represent the 95% CI. The combined OR in the random-effects model was 1.68 (CI = 1.34–2.12).
  • y 25, 2011K2:! %;326%</;:368J% 263T8%/5%8;6:P84I% 8%3234IQ8%;32;81% 78%;/85Q J% [51/D%11/1%34</% 2;8%N3<% /1%J3:1I%K2:! %;326% 8% J/<8%X 436:/2%6/% ^@% E06%183<% 678%5/1% 83;7% K8%51/D% % *D@!M@! 8436:P8%1:<T<%/5%R1/<6368%;32;81%;/DR31:2K%678%7:K78<6%N:67%678%4/N8<6% c ! %82%J3:1I% ;34;:0D%:263T8%;368K/1:8<?%% MP, Tucker KL. J Natl%l%R//48J%18436:P8%1:<T<%5/1%344%<:U%<60J:8<?% Gao X, LaValley "$$5.C!>$)15% Cancer Inst. 2005 Dec 7;97(23):1768-77.N782%N8% % $$5.!J%l%R//48J%18436:P8%1:<T%:2;40J:2K%678%<60JI%EI%_31/2%86%34?%% ! ;! 0%"$$5.!M!% % " % :> < %% l
  • MILK, CA & PROSTATE CANCER1.  Raimondi S, Mabrouk JB, Shatenstein B, Maisonneuve P, Ghadirian P. Diet and prostate cancer risk with specific focus on dairy products and dietary calcium: a case-control study. Prostate. 2010 Jul 1;70(10):1054-65.2.  Butler LM, Wong AS, Koh WP, Wang R, Yuan JM, Yu MC. Calcium intake increases risk of prostate cancer among Singapore Chinese. Cancer Res. 2010 Jun 15;70(12):4941-83.  Kurahashi N, Inoue M, Iwasaki M, et al. Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men. Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):930-7.4.  Ahn J, Albanes D, Peters U, et al. Dairy products, calcium intake, and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev. 2007 Dec;16(12):2623-30.5.  Mitrou PN, Albanes D, Weinstein SJ et al. A prospective study of dietary calcium, dairy products and prostate cancer risk (Finland). Int J Cancer; 120(11):2466-73, 2007.6.  Rohrmann S, Platz EA, Kavanaugh CJ, et al. Meat and dairy consumption and subsequent risk of prostate cancer in a US cohort study. Cancer Causes Control. 2007 Feb;18(1):41-50.7.  Gao X, LaValley MP, Tucker KL. Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J Natl Cancer Inst. 2005 Dec 7;97(23):1768-77.
  • BREAST CANCER
  • INCONCLUSIVE EVIDENCE•  Missmer SA, Smith-Warner SA, Spiegelman D, et al. Meat and dairy food consumptionand breast cancer: a pooled analysis of cohort studies. Int J Epidemiol 2002;31:78-85.•  Moorman PG, Terry PD. Consumption of dairy products and the risk of breastcancer: a review of the literature. Am J Clin Nutr 2004; 80: 5-14.•  Michels KB, Mohllajee AP, Roset-Bahmanyar E, Beehler GP, Moysich KB. Diet andbreast cancer, a review of the prospective observational studies. Cancer 2007;109(12 Suppl): 2712–2149.•  Cho E, Spiegelman D, Hunter DJ, Chen WY, Stampfer MJ, Colditz GA, Willett WC. ControloPremenopausal fat intake and risk of breast cancer. J Natl Cancer Inst 2003; 95:1079-1085.•  Shin M, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of dairyproducts, calcium and vitamin D and risk of breast cancer. J Natl Cancer Inst 2002;94: 1301-1311.
  • OVARIAN CANCER
  • Modest elevation inthe risk of ovariancancer was seen forlactose intake ~ to 3+servings of milk per Controloday Genkinger JM, Hunter DJ, Spiegelman D, et al. Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):364-72.
  • COLON CANCER
  • review Annals of O A A 1.2 Relative R Study (95% CI) Kampman, 1994 0.86 ( 0.57 1 Martinez, 1996 0.89 ( 0.56 Estimated RR .8 Jarvinen, 2001 0.72 ( 0.33 McCullough, 2003 0.96 ( 0.78 This meta-analysis shows that Sanjoaquin, 2004 1.10 ( 0.65 .6 milk and total dairy Kesse, 2005 0.54 ( 0.33 Lin, 2005 1.12 ( 0.72 Larsson, 2006 0.67 ( 0.51 products, but not cheese or Park, 2007 0.81 ( 0.70 .4 0 200 400 600 800 1000 1200 other dairy products, are Lee, 2009 0.80 ( 0.50 Total dairy products (g/day) Overall 0.83 ( 0.74 Best fitting fractional polynomial associated with a 95% confidence interval .25 .5 .75 1 2 reduction in Relative Risk B colorectal cancer B 1.2 Relative R Study (95% CI) 1 risk. Kampman, 1994 0.92 ( 0.7 Estimated RR .8 Jarvinen, 2001 0.91 ( 0.7 McCullough, 2003 0.94 ( 0.8 Sanjoaquin, 2004 1.00 ( 0.7 .6 Kesse, 2005 0.78 ( 0.5 Lin, 2005 1.03 ( 0.8 Larsson, 2006 0.81 ( 0.7 .4 0 100 200 300 400 500 600 700 800 Park, 2007 0.91 ( 0.8 Total milk (g/day) Lee, 2009 0.81 ( 0.5 Best fitting fractional polynomial Overall 0.90 ( 0.8 95% confidence interval Aune D, et al. Ann Oncol. 2011 May 26 .25 .5 .75 1 2Figure 3. Total dairy products and total milk and colorectal cancer,nonlinear dose–response. RR, relative risk. Relative Risk
  • OTHER TYPES OF CANCERStang A, BAUMGARDT-ELMS, C. et al. Adolescent milk fat and galactose consumption and testicular germ cell cancer. Cancer Epidemiol Biomarkers Prev; 15(11):2189-95, 2006.Ganmaa D, Li XM, Qin LQ, et al. The experience of Japan as a clue to the etiology of testicular and prostatic cancers. Med Hypotheses. 2003 May;60(5):724-30.Bravi F, Bosetti C, Scotti L, et al. Food groups and renal cell carcinoma : a case-control study from Italy. Int J Cancer. 2007 Feb 1;120(3):681-5.Peters ES, Luckett BG, Applebaum KM, Marsit CJ, McClean MD, Kelsey KT. Dairy products, leanness, and head and neck squamous cell carcinoma . Head Neck. 2008 Sep;30(9):1193-205.
  • MILK & ACNE (Epidemiology) Adebamowo CA, Spiegelman D, Danby FW, et al High school dietary dairy intake and teenage acne. J Am Acad Dermatol; 52(2):207-14, 2005. Adebamowo CA, Spiegelman D, Berkey CS, et al. Milk consumption and acne in adolescent girls. Dermatol Online J; 12(4):1, 2006. Dose Extra Batata Doce Adebamowo CA, Spiegelman D, Berkey CS, et al. Milk consumption and acne in teenaged boys. J Am Acad Dermatol. Controlo 2008 May;58(5):787-93
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