AHS Slides_Pedro Bastos

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

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%"


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

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!


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”."


PURPOSE OF MILK


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

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.

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

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


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
IR = 0.34) were m
than their relative
2H, P < 0.05). Th

with the finding th
GH-deficient m
versus 4.4 mU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulin serum insulin c
insulin-sensitive
Although GH
INTRODUCTION of age-dependent mutations and neoplastic disease (20–23). Among cardiac dis
vated
the mortality from
bining cardiac dis

be similar to that
SCH9, the homolog of mammalian S6K (S6 kinase), protect against functions of the IGF-1 pathway underlie its putative roledeaths in relative
in cancer
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-
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

Cancer, and Diabetes in Humans


0

INTRODUCTION
Cases

of age-dependent mutations and neoplastic disease (20–23). Among
Guevara-Aguirre J, et al. Sci Transl Med 2011, 3:1-9.

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

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


CASEIN PER LITER
Grs

25

20

15 COW’S
MILK

10

5 HUMAN
MILK
0


•  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

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

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.

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%

FERMENTATION"
!!
!!
!
!!
!!
!!
"
""
"
"Reduces IGF-1 (measured in whey) by 20%"
""

"
"
!


Melnik BC, Schmitz G. Exp Dermatol. 2009 Oct;18(10):833-41

Wilkinson SB, et al. Am J Clin Nutr. 2007 Apr;85(4):1031-40

Elevated 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




INTRODUCTION of age-dependent mutations and neoplastic disease (20–23). Among
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



1

0


Case
Cases

INTRODUCTION of age-dependent mutations and neoplastic disease (20–23). Among
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.
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 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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