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MILK, DAIRY AND HUMAN HEALTH




Los Angeles, August 2011   Pedro Carrera Bastos
HISTORY OF MILK & DAIRY

           "
ists (Table 2)26,67–69 when compared with current optimal                                                8. Lo
      values defined by health institutions ( 120 mm Hg                                                            par

Table 1 Historical milestones in human generations14,63–65                                                     Table
                                                                                                               Yanom
Historical milestones                                         Generations                         % total
Homo habilis                                                  76,667                              100.0        Age (ye
Homo erectus                                                  60,000                              78.2         0–9
Modern Homo sapiens                                           6666                                8.7          10–19
Neolithic Revolution                                          366                                 0.48         20–29
Industrial Revolution                                         7                                   0.009        30–39
Food industry (junk food) and                                 4                                   0.005        40–49
physical inactivity (Modern Age)                                                                               50




16            submit your manuscript | www.dovepress.com
 Carrera-Bastos P, Fontes-Villalba M, O'Keefe 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	
  




                                                                                                                                                                      Present
Generations
  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° E
gure 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 only
13910*T, associated to LP. Dots represent sample data taken from a previous review [14,26–30]; crosses represent
r 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 BP
equency 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 divergent
Origin 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 = 81

dofanian        Tanzania                                                                            Nige
                           Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-40
61
AHS Slides_Pedro Bastos
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)
 Lbs
25000!


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 nutrition

reduced the
average age   at
first lactation"



                Hare E, Norman HD, Wright JR. J Dairy Sci 2006; 89: 365-370.
The es
                                        Modern milking
                                                                                                                                                                         Estrone
 I don't 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 May

inseminated 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, 2006


milk secretion. Milking is stopped for 60 days just before the next                                                      2
                                                                                                                                 body it is convert
delivery, which is referred to as the "dry period." The cow is                                                                   has a high oral
slaughtered after giving birth to 4 or 6 calves. Modern cows are                                                                       Milk con
                                                                                                                                 Premarin, which
milked for 7 or 8 months while they are pregnant, including the                                                                        amount o
                                                                                                                                 contains naturally
latter 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 estro
comment 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
                                                                                               calf
bovine 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 and

However, 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, MD
Children’s Hospital Oakland Research                                University of California at Los Angeles, Los
Institute, Oakland, CA!                                             Angeles, CA
"
Lawrence J. Appel, MD, MPH"                                         Penny M. Kris-Etherton, PhD, RD
Johns Hopkins Medical Institutions,                                 Penn State University, University Park, PA
Baltimore, MD!
"                                                                   Joanne R. Lupton, PhD
Yvonne L. Bronner, ScD, RD, LD"                                     Texas A&M University, College Station, TX
Morgan State University, Baltimore, MD!
"                                                                   Theresa A. Nicklas, DrPH, MPH, LN
Benjamin Caballero, MD, PhD"                                        Baylor College of Medicine, Houston, TX
Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD!                                              Russell R. Pate, PhD
"                                                                   University of South Carolina, Columbia, SC
Carlos A. Camargo, MD, DrPH"
Harvard University, Boston, MA!                                     F. Xavier Pi-Sunyer, MD, MPH
"                                                                   Columbia University, New York, NY
Fergus M. Clydesdale, PhD,"
University of Massachusetts, !Amherst,                              Connie M. Weaver, PhD
Amherst, 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 of
Americans.”

“... So in a world                       where
you are tryingto
increase calcium
intake and simultaneously
increase potassium and,                                                     Carlos Camargo, MD, DrPH
perhaps Vitamin D; milk                                                     Harvard University, Boston, MA


looks 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 women
from 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 than
100,000 separate molecules,
the levels of which vary with
the 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 & INSULIN




Last 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 CHO
has 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
                                                      carbohydrates

Ostman EM, et al. Am J Clin Nutr 2001;74:96 –100

Hoyt G et al. Br J Nutr. 2005 Feb;93(2):175-7
IS THIS BENEFICIAL?
Whey Proteins




GLP-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):70-5

Del 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
%

120,00

100,00

 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 ARTICLE
988 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 of
nd 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 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.
                                                                                               0	
  	
  
INTRODUCTION
                                                                                             Cases	
  
                                                                        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-
                       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 of
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
July 2011                                                                                   GLP-1–BASED THE
Elashoff 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 to
the 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 LITER
Grs

25


20


15                         COW’S
                            MILK

10


 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 rats


Xian 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
                            Adults


Norat 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, 12:84-89

Holmes 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):1211-6




Gunnell D, Oliver SE, Peters TJ, et al. Are diet prostate cancer
associations mediated by the IGF axis?. A cross-sectional
analysis of diet, IGF-I and IGFBP-3 in healthy middle-aged
men. 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.htm




75º 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
AHS Slides_Pedro Bastos
Wilkinson SB, et al. Am J Clin Nutr. 2007 Apr;85(4):1031-40
Elevated plasma
IGF-1/ IGFBP-3 ratio
represents a risk factor for

certain epithelial                     cell
cancers"

     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/onc

REVIEW

Emerging role of insulin-like growth factor receptor inhibitors in oncology:
early clinical trial results and future directions

A Gualberto1,2 and M Pollak3
1
Clinical Department, Pfizer Oncology, New London, CT, USA; 2Department of Pathology, Brown University Alpert School of
Medicine, Providence, RI, USA and 3Department of Oncology, McGill University, Montreal, Quebec, Canada




Preclinical 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; Hartog
has 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; Yuen
from 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 theme
to many tumor types, and early results have justified          that emerged from this work was the notion that
expanded 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 cellular
candidates 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 resistance
reveal 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 in
14 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 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
                                                            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). 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 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)–deficient
1
 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 Laron
Prevalence of malignancy in                   the
                                                congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect were
four 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 DAIRY




Bastian 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/ ml
Total Saliva Secretion: 691 ml/24 hours

EGF 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
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AHS Slides_Pedro Bastos

  • 1. MILK, DAIRY AND HUMAN HEALTH Los Angeles, August 2011 Pedro Carrera Bastos
  • 2. HISTORY OF MILK & DAIRY
 "
  • 3. ists (Table 2)26,67–69 when compared with current optimal 8. Lo values defined by health institutions ( 120 mm Hg par Table 1 Historical milestones in human generations14,63–65 Table Yanom Historical milestones Generations % total Homo habilis 76,667 100.0 Age (ye Homo erectus 60,000 78.2 0–9 Modern Homo sapiens 6666 8.7 10–19 Neolithic Revolution 366 0.48 20–29 Industrial Revolution 7 0.009 30–39 Food industry (junk food) and 4 0.005 40–49 physical inactivity (Modern Age) 50 16 submit your manuscript | www.dovepress.com Carrera-Bastos P, Fontes-Villalba M, O'Keefe JH, Lindeberg S, Cordain L. Res Rep Clin Cardiol 2011;2:15-35. Dovepress
  • 4. 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   Present Generations 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
  • 5. 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° E gure 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 only 13910*T, associated to LP. Dots represent sample data taken from a previous review [14,26–30]; crosses represent r 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 BP equency 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
  • 6. 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 divergent Origin 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
  • 7. 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
  • 8. 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 = 81 dofanian Tanzania Nige Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-40 61
  • 10. 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
  • 11. 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
  • 12. MILK PRODUCTION PER COW (USA) Lbs 25000! 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
  • 13. RBGH INCREASES MILK PRODUCTION" "" Bauman DE, Eppard PJ, DeGeeter MJ, Lanza GM. J Dairy Sci. 1985 Jun;68(6):1352-62
  • 14. INDUSTRIAL MODEL OF DAIRYING" Change in nutrition reduced the average age at first lactation" Hare E, Norman HD, Wright JR. J Dairy Sci 2006; 89: 365-370.
  • 15. The es Modern milking Estrone I don't 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 May inseminated 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, 2006 milk secretion. Milking is stopped for 60 days just before the next 2 body it is convert delivery, which is referred to as the "dry period." The cow is has a high oral slaughtered after giving birth to 4 or 6 calves. Modern cows are Milk con Premarin, which milked for 7 or 8 months while they are pregnant, including the amount o contains naturally latter 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 estro comment 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 calf bovine 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 and However, it is insemination dairy farmers in Japan do not use this *Artificial said that Pregnancy Dry had given birth to 10 calves.
  • 16. “3 Cups per day of fat-free or low-fat milk and milk products”
  • 17. 2005 DIETARY GUIDELINES ADVISORY COMMITTEE
 Janet King, PhD, RD (Chair)" ! Vay Liang W. Go, MD Children’s Hospital Oakland Research University of California at Los Angeles, Los Institute, Oakland, CA! Angeles, CA " Lawrence J. Appel, MD, MPH" Penny M. Kris-Etherton, PhD, RD Johns Hopkins Medical Institutions, Penn State University, University Park, PA Baltimore, MD! " Joanne R. Lupton, PhD Yvonne L. Bronner, ScD, RD, LD" Texas A&M University, College Station, TX Morgan State University, Baltimore, MD! " Theresa A. Nicklas, DrPH, MPH, LN Benjamin Caballero, MD, PhD" Baylor College of Medicine, Houston, TX Johns Hopkins Bloomberg School of Public Health, Baltimore, MD! Russell R. Pate, PhD " University of South Carolina, Columbia, SC Carlos A. Camargo, MD, DrPH" Harvard University, Boston, MA! F. Xavier Pi-Sunyer, MD, MPH " Columbia University, New York, NY Fergus M. Clydesdale, PhD," University of Massachusetts, !Amherst, Connie M. Weaver, PhD Amherst, 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
  • 18. WHY 3 CUPS OF MILK?" “... the focus was, of course, the low calcium intake of Americans.” “... So in a world where you are tryingto increase calcium intake and simultaneously increase potassium and, Carlos Camargo, MD, DrPH perhaps Vitamin D; milk Harvard University, Boston, MA looks 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
  • 19. MILK, CALCIUM & FRACTURES
  • 20. 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
  • 21. Bolland MJ, et al. BMJ. 2008 Feb 2;336(7638):262-6
  • 22. MILK AND FRACTURES! No association in observational studies among adults RR/+1glass! Pooled analysis for categories of milk intake and hip fracture risk in women from 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"
  • 23. 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
  • 24. WHAT IS MILK?" Milk is a complex fluid, containing more than 100,000 separate molecules, the levels of which vary with the 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
  • 25. 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
  • 26. 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
  • 27. HOW DOES MILK ACHIEVE THIS PURPOSE?
  • 28. GI & INSULIN Last AR, Wilson SA. Am Fam Physician 2006;73:1942-8
  • 29. Gannon MC, Nuttall FQ, Krezowski PA, Billington CJ, Parker S. Diabetologia. 1986 Nov;29(11):784-91.
  • 30. 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.
  • 31. Milk (200 ml) + low GI CHO has an insulin response ~ white bread Liljeberg Elmstahl H & Bjorck I. Eur J Clin Nutr 2001; 55:994–999.
  • 32. WHOLE MILK VS SKIM MILK Glucose SKIM MILK WHOLE MILK Hoyt G et al. Br J Nutr. 2005 Feb;93(2):175-7
  • 33. Consumption of milk induces a reactive hypoglycaemia similar to high glycaemic load carbohydrates Ostman EM, et al. Am J Clin Nutr 2001;74:96 –100 Hoyt G et al. Br J Nutr. 2005 Feb;93(2):175-7
  • 35. Whey Proteins GLP-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.
  • 36. Pratley RE, Gilbert M. Rev Diabet Stud. 2008 Summer;5(2):73-94
  • 37. Insulin Hyperinsulinemia Resistance??? Rizza RA, et al. Diabetologia. 1985 Feb;28(2):70-5 Del 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.
  • 39. 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
  • 41. 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
  • 42. % 120,00 100,00 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
  • 43. Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen KF. Eur J Clin Nutr. 2009 Sep;63(9):1076-83
  • 44. %   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
  • 45. 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 ARTICLE 988 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
  • 46. 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 of nd 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-
  • 47. 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. 0     INTRODUCTION Cases   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- 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 of 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
  • 48. July 2011 GLP-1–BASED THE Elashoff 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
  • 52. Published assays relate exclusively to the 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.
  • 53. 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
  • 54. CASEIN PER LITER Grs 25 20 15 COW’S MILK 10 5 HUMAN MILK 0 Park YW, Haenlein GFW. Handbook of milk of non-bovine mammals. Blackwell Publishing, 2006
  • 55. •  Casein and, to a lesser degree, BSA & Lactoferrin prevent IGF-1 Proteolysis in rats Xian CJ, Shoubridge CA, Read LC. J Endocrinol. 1995 Aug;146(2):215-25.
  • 56. RBGH INCREASES MILK IGF-1" "" Faulkner A. J Dairy Res. 1999 May;66(2):207-14.
  • 57. 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.
  • 58. 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.
  • 59. MILK INCREASES IGF-1 IN HUMANS Estudo de intervenção N= 82 moças caucasianas com 12 anos Duração: 18 meses 10-20% Increase in Adults Norat 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, 12:84-89 Holmes MD, et al. Cancer Epidemiol Biomarkers Prev 2002; 11: 852-861.
  • 60. 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):1211-6 Gunnell D, Oliver SE, Peters TJ, et al. Are diet prostate cancer associations mediated by the IGF axis?. A cross-sectional analysis of diet, IGF-I and IGFBP-3 in healthy middle-aged men. Br. J Cancer 2003; 88: 1682-1686.
  • 61. 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
  • 62. 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.
  • 63. PASTEURIZATION" 121ºC for 15 min reduces IGF-1 to virtually undetected levels Collier RJ, et al. J Dairy Sci 1991; 74:2905-2911
  • 64. PASTEURIZATION" Yogurt: " ü 85ºC for 30 min" ü 95ºC for 10 min" " http://www.milkfacts.info/Milk%20Processing/Milk%20Processing%20Page.htm 75º for 15 min decreases IGF-1 by 45% Kang SH, et al. J Dairy Sci 2006; 89: 402-409.
  • 65. FERMENTATION" !! !! ! !! !! !! " "" " "Reduces IGF-1 (measured in whey) by 20%" "" " " ! Kang SH, et al. J Dairy Sci 2006; 89: 402-409.
  • 66. Melnik BC, Schmitz G. Exp Dermatol. 2009 Oct;18(10):833-41
  • 68. Wilkinson SB, et al. Am J Clin Nutr. 2007 Apr;85(4):1031-40
  • 69. Elevated plasma IGF-1/ IGFBP-3 ratio represents a risk factor for certain epithelial cell cancers" Cordain L. et al. Comparative Biochemistry and Physiology Part A 2003; 136: 95–112
  • 70. Oncogene (2009), 1–13 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc REVIEW Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions A Gualberto1,2 and M Pollak3 1 Clinical Department, Pfizer Oncology, New London, CT, USA; 2Department of Pathology, Brown University Alpert School of Medicine, Providence, RI, USA and 3Department of Oncology, McGill University, Montreal, Quebec, Canada Preclinical 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; Hartog has 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; Yuen from 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 theme to many tumor types, and early results have justified that emerged from this work was the notion that expanded 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 cellular candidates 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 resistance reveal 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
  • 71. 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 in 14 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
  • 72. 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
  • 73. 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 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). 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 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)–deficient 1 Institute of Endocrinology, Metabolism and Reproduction, Quito, Ecuador. 2Depart- mice (29–32), and GH replacement therapy can exacerbate insulin re-
  • 74. 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 Laron Prevalence of malignancy in the congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect were four 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
  • 76. BETA-CELLULIN IN DAIRY Bastian SE, et al. Measurement of betacellulin levels in bovine serum, colostrum and milk. J Endocrinol. 2001 Jan;168(1):203-12.
  • 77. 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.
  • 78. EGF in saliva: 0.0512 ng/ ml Total Saliva Secretion: 691 ml/24 hours EGF 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.
  • 79. EGF upregulates its own receptor Increased signalling Cordain L. U.S. Dermatology Review II 2006, (Ed.,Bedlow, J). Touch Briefings Publications, London, 2006