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UWS Master of Science in Nutrition and
           Functional Medicine




 Course: Supplementation and Whole Food
  Nutrition
 Week #: 4
 Topic: Milk, Dairy and Human Health
 Instructor: Pedro Carrera Bastos, MS
OBJECTIVES FOR THIS WEEK
 To understand the evolutionary pressures behind Adult lactase persistence
 To recognize that Milk is a mammalian signaling system, with various
  hormonal effects
 To know the current scientific evidence concerning Dairy, Metabolic
  Syndrome and Cancer
 To understand the potential value of Dairy and/or its Proteins in Exercise
  Performance
 To know the current evidence regarding Dairy and Body Composition
 To understand the mechanisms behind Milk and Acne
 To know the Casein A1/A2 controversy
 To recognize the main differences between raw milk and
  pasteurized/homogenized milk
 To understand the role of Calcium in Osteoporosis and Cardiovascular
  Disease
 To recognize Milk Allergy
 To understand the connection between Milk proteins and auto-immune
  diseases
 To learn to prepare lactose/dairy-free, rich-calcium meals, and to know how to
  ferment milk
TOPICS FOR THIS PRESENTATION


Evolutionary History of Milk and
 Dairy

Lactose Intolerance and ALP
HISTORY OF MILK & DAIRY
ORIGINS OF MAN
                       Homo sapiens
                  0                                H. heidelbergensis
                                                                 H. erectus                                                 Paranthropus
                      H. neanderthalensis
                                                                                                                            boisei
                  1
                                            H. antecessor                             H. habilis          P. robustus


                  2
                                                            H. ergaster                       Au. garhi
                                                                        Au.
                  3                                                     rudolfensis                                   P. aethiopicus
Milhões de anos




                                                    Kenyanthropus                                           Au. africanus
                                                    platyops    Au.
                                                                bahrelghazali
                  4                                                                                                            Ardipithecus
                                                                                                                               ramidus
                                                                                                      Au. afarensis
                                                                                 Au.
                                                                                 anamensis
                  5

                                                                                                                                 Orrorin
                                                                                                                                 tugenensis
                  6



                  7
                                                                                                                        Sahelanthropus
                                                                                                                        tchadensis


                  8



                                  Adapted from Wood B. Nature 2002:418:133-35 & from Cordain L, 2009
All humans in
   Europe, Asia, Oceania and
        America have an
                      AFRICAN ORIGIN                                                                                            Etiópia




             LESS GENETIC DIVERSITY                                                                            Liu H, et al., 2006

                 OUTSIDE AFRICA

Relethford JH. Heredity. 2008 Jun;100(6):555-63.         Jakobsson M, et al. Nature 2008; 451(7181):998-1003

Manica A, et al. Nature; 2007; 448(7151):346-8           Hellenthal G, Auton A, Falush D. PLoS Genet. 2008 May 23;4(5):e1000078

Liu H, et al. Am J Hum Genet. 2006 Aug;79(2):230-7       Ramachandran S, et al. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15942-7

Conrad D, et al. Nat Genet 2006; 38: 1251–1260           Prugnolle F, Manica A, Balloux F. Current Biology 2005; 15:R159–R160

RAY N, et al. Genome Res 2005; 15:1161–1167              Cavalli-Sforza LL, Feldman MW. Nat Genet 2003; 33:266–275

Macaulay V, et al. Science 2005; 308(5724):1034-6        Tishkoff S, Williams S. Nat Rev Genet 2002; 3: 611–621

Currat M, Excoffier L. PLoS Biology 2004; 2: 2264–2274   Harpending, H, Rogers, AR. Annu Rev Genomics Hum Genet 2000; 1:361–385
Liu H, et al. Am J Hum Genet. 2006 Aug;79(2):230-7
WHAT WAS OUR ECOLOGICAL
       NICHE???
HUNTER-GATHERER’S DIETS
VEGETABLE SOURCES


 Plants

 Roots & Tubers

 Berries

 Fruits

 Nuts


             Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54
ANIMAL SOURCES


                                               Wild Animals
                                               Insects
                                               Seafood
                                               Eggs




Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54
WHAT THEY DIDN’T EAT?
DAIRY




REFINED SUGARS                           SALT                           LEGUMES                           CEREALS




      ALCOHOL                             FEEDLOT MEAT                                 REFINED VEGETABLE OILS

                             Cordain L. Implications of Plio-Pleistocene Hominin Diets for Modern Humans.
 In: Early Hominin Diets: The Known, the Unknown, and the Unknowable. Ungar, P (Ed.), Oxford University Press, Oxford, 2006, pp 363-83
MILK? WHY NOT?




Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54
meses   meses   meses




Sellen DW. J Nutr. 2001 Oct;131(10):2707-15
BREASTFEEDING PATTERNS




     Sellen DW. J Nutr. 2001 Oct;131(10):2707-15
~11,000 YA
                                   Neolithic
                                   Revolution
                                   in the Middle
                                   East



Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54.

Dubreuil L. Journal of Archaeological Science 2004; 31(11): 1613-1629.

Bar-Yosef O. Evol Anthropol 1998;6:159 –77.
EVIDENCE FOR THE USE OF DAIRY IN
                                                 THE MIDDLE EAST




                                                First evidence of dairying in the Middle East (Turkey) 4

                             Domestication of sheeps, goats and cattle (Middle East) 1-3




                                                                                                                              Present
                    10,000



                                  9,000



                                                8,000



                                                              7,000



                                                                           6,000



                                                                                      5,000



                                                                                              4,000



                                                                                                      3,000



                                                                                                              2,000



                                                                                                                      1,000
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.
GEOGRAPHIC EXPANSION OF THE FIRST NEOLITHIC
               CULTURES




       Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
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

                             Domestication of sheeps, goats and cattle (Middle East) 1-3




                                                                                                                                             Present
                    10,000



                                  9,000



                                                8,000



                                                              7,000



                                                                           6,000



                                                                                          5,000



                                                                                                    4,000



                                                                                                               3,000



                                                                                                                         2,000



                                                                                                                                     1,000
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
UVB




Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
UVA




Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
FOLATE




Miller AL, Kelley GS. Altern Med Rev. 1996;1(4):220-235
 5MTHF absorbs UVB 
  oxidized to 5MDHF

 5MDHF doesn’t re-enter the
  Folate pool

 5MTHF is oxidized by ROS
  produced by naturally
  photosensitizers
  (flavins, porphyrins, bilirubin,
   etc.) after UVA exposure
Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
PIGMENTATION AND LATITUDE




  Chaplin G. Am J Phys Anthropol. 2004 Nov;125(3):292-302
Liu H, et al. Am J Hum Genet. 2006 Aug;79(2):230-7
Holick MF. J Clin Invest. 2006 Aug;116(8):2062-72
Vitamin D deficiency 6 + months per year

Vitamin D deficiency 1 + months per year


       Vitamin D all year

Vitamin D deficiency 1 + months per year

Vitamin D deficiency 6 + months per year


      Jablonski NG, Chaplin G. J Hum Evol. 2000 Jul;39(1):57-106
Low
                                                                   Pigmentation

54 mJ/cm2
                                                                   Pele muito
                                                                   pigmentada



                                                                   Pele muito
320 mJ/cm2                                                         pigmentada




             Holick M. Am J Clin Nutr 2004;80(suppl):1678S– 88S.
Low
                                                                   Pigmentation

54 mJ/cm2
                                                                       High
                                                                   Pigmentation



                                                                   Pele muito
320 mJ/cm2                                                         pigmentada




             Holick M. Am J Clin Nutr 2004;80(suppl):1678S– 88S.
Low
                                                                   Pigmentation

54 mJ/cm2
                                                                       High
                                                                   Pigmentation



                                                                       High
320 mJ/cm2                                                         Pigmentation




             Holick M. Am J Clin Nutr 2004;80(suppl):1678S– 88S.
FOOD SOURCES OF VITAMIN D

                  Food                                    Vit. D (IU)

Cod Liver Oil (10 g)                                           1360
Sardins (105 g)                                                 500
Tuna (105 g)                                                    402
Farmed Salmon (105 g)                                           360
Egg (1 medium)                                                  20
Liver (105 g)                                                   15



       Ozkan B. J Clin Res Pediatr Endocrinol. 2010 Dec;2(4):137-43
Holick MF. J Clin Invest. 2006 Aug;116(8):2062-72
Pelvic flattening, permanently narrowing
              the birth canal




INCREASED MATERNAL MORTALITY DURING CHILDBIRTH


             Jablonski NG et al. J Hum Evol. 2000;39(1):57-106
VDR IN MULTIPLE CELLS




  Holick MF. J Clin Invest. 2006 Aug;116(8):2062-72
Zasloff M. Nat Med. 2006 Apr;12(4):388-90
DEPIGMENTATION




           Darker




Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult
lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B.
                 Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
UVA IS HIGHER IN THE POLES & SNOW REFLECTS UVA




         Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
TF – Traditional Foods
1 mcg Vit D = 40 IU




                         Kuhnlein HV, Receveur O. J Nutr. 2007 Apr;137(4):1110-4
HIGH LATITUDE, CLOUDY
CLIMATE, REDUCED SUNLIGHT


                                                                N 65




DECREASED UV EXPOSURE &                                          N 55


LESS VITAMIN D SYNTHESIS
                                                                 N 45




                                         RICKETS


                            Loomis WF. Science. 1967 Aug 4;157(788):501-6.
                            Jablonski NG et al. J Hum Evol. 2000;39(1):57-106
GEOGRAPHIC EXPANSION OF THE FIRST NEOLITHIC
               CULTURES




       Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
THE SPREAD OF AGRICULTURE FROM THE MIDDLE EAST TO
N. EUROPE BROUGHT NOT ONLY DAIRYING BUT ALSO



 WHEAT & BARLEY
                                5000 YA


                                           6000 YA

                                                         8000 YA           Jericho
                                                                           10,000 YA
                                                                 9000 YA




                Cordain, L., Hickey, M. S. & Kim, K. In press.
The circum North/Baltic Seas land mass is warmed because of
  1) Gulf Stream
  2) Maritime nearness



       Mar do                  Mar
       Norte                  Báltico
                       55 N




                                                           Average Temperature in Winter in
                                                           London is 4 C vs - 9 C in N.
                                                             America & Eurásia, at 51º N


      Seager R. The source of Europe’s mild climate. Am Sci 2006;94;334-41 . In Cordain, L., Hickey, M. S. & Kim, K. In press.
Cordain L. World Rev Nutr Diet. 1999;84:19-73
 High consumption (>50% energy)
                                                           of whole grains (whole
                                                           wheat, maize, oats, rye) are
                                                           routinely used to induce rickets in
                                                           dogs, rats, chickens and
                                                           primates1-4

                                                          Epidemiological studies of human
                                                           populations consuming high
                                                           intakes of unleavened bread
                                                           show rickets and vitamin D
                                                           deficiency to be widespread 5-7




1Mellanby E. Lancet 1919;1:407-08.
2Thomas  BH et al. Biochem J 1936;30:12-177-88
3Sly MR et al. Calcif Tissue Int 1984;36:370-79
4Grammer JC et al. Poult Sci 1983;62: 103-9
5Gibson RS et al. Brit J Nutr 1987;58:23-29
6Brooke OG et al. Brit J Obstet Gynaecol 1981;88:18-26
7Hunt SP et al. BMJ 1976;2:1351-54.



          In Cordain L. World Rev Nutr Diet. 1999;84:19-73
HOW WHOLE GRAINS MAY PROMOTE RICKETS?
 Increased elimination of vitamin D in bile1

 Low Ca/P thereby promoting bone resorption2

 Impaired labile calcium absorption via high
  phytate content3

 Lectin (WGA) blockade of the nuclear
  pore, thereby preventing gene transcription of
  VDR4,5




                                        1Batchelor AJ et al. Brit J Nutr 1983;49:213-16
                                        2Cordain L. World Rev Nutr Diet. 1999; 84:19–73
                                        3Mellanby E. J Physiol 1949;109:488-533
                                        4Guinex C. et al. Int J Biochem Cell Biol 2005;37:765-74
                                        5Findlay DR et al. J Cell Biol 1987;104:189-200
WGA

   Wheat Germ: 300 – 350 mg/kg WGA (1)
   Whole Wheat Flour: 30-50 mg/kg WGA (2)
   Refined Wheat Flour: 4.4 mg/kg WGA (2)




           1. Vincenzi S, et al. J Agric Food Chem. 2002 Oct 23;50(22):6266-70.

           2. Matucci A et al. Food Control 2004;15: 391-95
Extreme Dermal Depigmentation
                                           originated in Northern Europeans

                                               ~ 5,300 – 6,000 years




                                 GEOGRAPHIC DISTRIBUTION FOR SKIN PIGMENTATION




Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult
lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B.
                 Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
GEOGRAPHIC DISTRIBUTION FOR HAIR & EYE
                PIGMENTATION IN EUROPE


                                Blond Hair / Blue Eyes originated
                                            in Europe

                                     ~ 6,000 – 10,000 YA




Eiberg H et al. Hum Genet 2008;123:177-187.

Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult
lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B.
Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
INCREASED CALCIUM INTAKE




 Pettifor JM. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1725S-9S
Adapted from Cordain L, 2009
                                                                                                          (with permission)




     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.
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.
BETA-CELLULIN




Bastian SE, et al. Measurement of betacellulin levels in bovine serum, colostrum and milk. J Endocrinol. 2001 Jan;168(1):203-12.
Adapted from Cordain L, 2009
                                                                                                                            (with permission)
EGF in saliva: 0.0512 ng/ ml
Total Saliva: 691 ml/24 hours

EGF in 24h 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.
Adapted from Cordain L, 2009
                                                                                                (with permission)




WGA can bind luminally
                                                                              BTC
expressed EGF-R                                                          or
                                                    WGA                             Lumen




                                           EGF Receptor

                                                          EGF Receptor
                                                                                                   To
                                                                                                   Lymph




                                                                                                   WGA



                 Hormi K et al. Cell Tissue Res 1994;278:439-50
                                                                                                   To
                 Rebbaa A et al. J Neurochem 1996;67:2265-2272
                                                                                               Circulation
                 Lochner N, et al. Pharm Res. 2003 May;20(5):833-9.
LACTOSE SOURCES


      Food                              Serving (g)                                 Lactose (g)
Cow’s Milk                                       100                                         4.6
Buffalo Milk                                     100                                         5.1
Goat’s Milk                                      100                                         4.1
Sheep’s Milk                                     100                                         5.4




        Park YW, Haenlein GFW. Handbook of Milk of Non-Bovine Mammals. Blackwell Publishing, 2006.
LACTOSE HYDROLYSIS




Lomer MC, Parkes GC, Sanderson JD. Aliment Pharmacol Ther. 2008 Jan15;27(2):93-103
LACTOSE SOURCES

      Food                              Serving (g)                                 Lactose (g)
Human Milk                                      100                                          6.9
Cow’s Milk                                       100                                         4.6
Buffalo Milk                                     100                                         5.1
Goat’s Milk                                      100                                         4.1
Sheep’s Milk                                     100                                         5.4


  LACTASE EXPRESSION IS COMMON IN MOST
            YOUNG MAMMALS
        Park YW, Haenlein GFW. Handbook of Milk of Non-Bovine Mammals. Blackwell Publishing, 2006.
After the weaning period is over, lactase
  production usually declines , although the
mechanisms and evolutionary reasons for this
downregulation are not fully understood
HIPOLACTASIA IS THE NORMAL PHENOTYPE
        IN HUNTER-GATHERERS
            AFTER AGE 3-5




   Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
Burger J, et al. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3736-41
LACTOSE INTOLERANCE
                      INTOLERÂNCIA À LACTOSE




HIGH OSMOTIC                                    HIGH OSMOTIC
    LOAD                                            LOAD




DIARRHEA                                        DIARRHEA




           Lomer MC, Parkes GC, Sanderson JD. Aliment Pharmacol Ther. 2008 Jan15;27(2):93-103
ALP IN EUROPE




             Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.




     Predicted Old World LP phenotype frequencies based on -13,910 C>T
                          allele frequency data only

                                                                                      Estimated Dates of Origin:
                                                                                                2188 - 20650 BP
(s = 0.014 - 0.150)                                                                             7450 - 12300 BP
THE HIGHEST FREQUENCY OF THE -13,910 C>T allele IS
 CENTERED CONCENTRICALLY WITHIN ~ 1000 KM RADIUS OF THE
                  NORTH & BALTIC SEAS

(between 53º and 58º N)

                                                                                           Baltic

                                             N. Sea




                                                                                                       (s = 0.090 - 0.190)




Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult
lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B.
                 Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
The combination of 1) high latitude, 2) cloudy weather, 3)
whole grain cereals as staples likely represented the unique
combination of selective pressures responsible for the
evolution of:

               ALP                                    Blond Hair/Blue Iris                 Extreme Dermal Depigmentation




    (5,000 – 12,000 YA)                           (6,000 – 10,000 YA)                                (5,300 – 6,000 YA)



  ALP: Ad libitum consumption of milk with GI distress protects
   against rickets by milk’s high calcium content1

  Blond hair & blue eyes; extreme dermal depigmentation enhances
   dermal synthesis of vitamin D and further protects against rickets2

    Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult
    lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B.
                     Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
Domestication of the Arabian camel: 6000 BP



Origin of G-13915 allele in the Arabian Pensinsula: 4000 BP




                     Enattah NS, et al. Am J Hum Genet. 2008 Jan;82(1):57-72
Spread of Pastoralism south
of the Sahara: 4,500 BP

Spread of Pastoralism
into Northern Tanzania: 3,300 BP




                   Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-40
Various SNPs (G/C-14010, T/G-
13915 and C/G-13907) associated
            with LP
 in Sub-Saharan Africans arose
                    000
         3000-7000 BP


             Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-40
20 N



                                                                           Equator


                                                                             20 S




 African children typically maintain normal plasma concentrations of
  vitamin D

 High selection coefficient (s) for putative LCT alleles in sub-Saharan
  Africans (s = 0.035-0.097)

 Is milk drinking protective of other pre-existing causes of mortality?


        Pfitzner MA et al. J Pediatrics 1998;133:740-4. In Cordain, L., Hickey, M. S. & Kim, K. In press.
MALARIA INCIDENCE




 MALARIA MORBIDITY AND MORTALITY WORLD WIDE ARE HIGHEST IN
                    SUB-SAHARAN AFRICA

 ~75% of all cases of P. falciparum malaria and >80% of all malaria
  attributable deaths occur in sub-Saharan Africa

                      Walther B et al. Ann Trop Med Parasitol 2007;101:657-72.
GENETIC CHANGES IN GEOGRAPHIC AREAS WHERE
                MALARIA IS ENDEMIC

 Hemoglobinopathies and
  other mutations influencing
  erythrocyte longevity
             Sickle cell anemia

             G6PD Deficiency

 ALP in parts of Africa where
  animal Trypanosomiasis
  doesn’t occur



 Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult
 lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B.
                  Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
Adapted from Cordain L, 2009
                                                                                          (with permission)

                                         MILK & MALARIA ???

                                                           All milk diets suppress malarial
                                                            infections in birds, rodents and
                                                            primates by restricting para
                                                            amino benzoic acid (PABA)
                                                            intake 1,2

                                                           The suppression of malarial
                                                            symptoms is abrogated when
                                                            supplemental PABA is added to
                                                            all milk diets or PABA deficient
                                                            diets of infected animals 2,3




1Kretschmar    W et al. Tropenmed Parasit 1973;24:51-59
2Nowell   F. Parasitology 1970;61:425-33.
3Kicska   GA et al. Infect Dis 2003;188:1776-81
Adapted from Cordain L, 2009
                                                                                                                           (with permission)
                                       PABA, FOLATE & MALARIA

Pentose phosphate cycle                               Glycolysis
                                                                                 PABA synthase activity in Plasmodia is
     D-Erythrose 4-P                          Phosphoenolpyruvate                 low & poorly supports growth1

                                                                                 Dietary deficiencies of PABA & folate
  7-Phospho-2-dehydro-3-deoxy-D-arabinoheptulosonate                              may suppress malarial symptoms by
                                          3-Dehydroquinate synthase               impairing folate metabolism1
                        3-Dehydroquinate
                                           3-Dehydroquinate dehydratase          Dietary PABA and folate reduce
                        3-Dehydroshikimate                                        efficacy of sulfa drugs in rodent
                                           Shikimate 5-Dehydrogenase              models2
                              Shikimate
                                           Shikimate kinase

                      Shikimate 3-Phosphate                                      MILK DOES NOT CONTAIN PABA & IS
                                           3-phosphoskikimate-1-carboxyvinyl
                                           transferase (EPSP synthase)                  A POOR SOURCE OF FOLATE
                3-Phospho-5-enoylpyruvylshikimate
                                                                                        (6-9 mg/100g vs. DRI 400 mg)3
     Ubiquinone           Chorismate              Aromatic Amino Acids
                                           PABA synthase

                                PABA
      Sulfonamides                         (additional PABA antagonizes sulfonamides)
                                                                                               1KicskaGA et al. Infect Dis 2003;188:1776-81
(inhibit plasmodial growth)
                               Folate                                                          2JacobsRL. Exp Parasitol 1964;15:213-25
                                                                                               3Johnston KE et al. J Food Sci 2002;67:817-20
ALP & MALARIA
 The pastoralist Fulani (>50 % ALP)
  exhibit resistance to malaria compared
  to other non-milk drinking African ethnic
  groups

 Unexplained by genetic resistance
  factors, but rather by enhanced
  immunity

 Displacement of PABA & Folate rich
  foods by milk may attenuate malaria
  infection while allowing immune
  exposure, thereby preventing serious
  symptoms & facilitate establishment of
  protective immunity

    Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult
    lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B.
                     Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
HIGH MILK INTAKE ASSOCIATED WITH HIGHER
            FOLATE RECEPTOR AUTOANTIBODIES




Risk (OR [95% CI]) of FR-autoantibodies for each quintile compared with the lowest quintile of milk intake in men and women



                                              J. Nutr. 139: 1037–1041, 2009
LACTOSE INTOLERANCE
PREVALENCE OF ALP IN VARIOUS
                              ETHNIC GROUPS

             80   76      75
             70
Percentage




             60
             50
             40
             30                      27           25
                                                               20
             20                                                          10
             10                                                               3
              0




                            Swallow DM. Ann Rev Genet 2003;37:197-219.
PREVALENCE OF ALP IN VARIOUS
                            EUROPEAN POPULATIONS

             100   90
              90        83 80
                              78
              80                   73 70
Percentage




              70                           65
                                                60 58
              60                                      55 52 52
                                                               50
              50                                                      40 40 38
              40                                                               35
              30                                                                    26 26 25

              20                                                                               15
                                                                                                    10
              10
               0




                                                 GRADIENT
                    NORTH WEST                                             SOUTH EAST

                                    Swallow DM. Ann Rev Genet 2003;37:197-219.
HIPOLACTASIA




http://nutrigenomics.ucdavis.edu/nutrigenomics/index.cfm?objectid=968814F6-65B3-C1E7-0C7007B71CC9959A
HIPOLACTASIA




   Occurs in
~ 65% of adults




       Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
LACTOSE INTOLERANCE                                          Abdominal Bloating (Small Bowell)

                                                                      Flatulence (Colon)




                                                                                             Constipation




   HIGH OSMOTIC                               HIGH OSMOTIC
       LOAD                                       LOAD




   DIARRHEA                                    DIARRHEA




        Lomer MC, Parkes GC, Sanderson JD. Aliment Pharmacol Ther. 2008 Jan15;27(2):93-103
DIAGNOSIS



                  Lactose


                      Milk



                                  Yogurt




Mataix J. Nutrición y Alimentación Humana – Tomo I: Nutrientes y Alimentos. Ergon, 2002.
LACTOSE FOOD SOURCES
          Food                                       Serving                                   Lactose (g)
Cow’s Milk                                            1 glass                                             11
Ice-Cream                                               150 g                                          9-10
Cottage Cheese                                          ~60 g                                            7-8
Parmesan                                                ~60 g                                            1-2
Gouda                                                   ~60 g                                            1-2
Camembert                                               ~60 g                                            0-1

          GOOD TOLERANCE UP TO 12 GRAMS

   Pribila BA, et al. J Am Diet Assoc. 2000 May;100(5):524-8.

   Shils M.E. et al. Modern Nutrition in Health and Disease. Lippincott Williams & Wilkins, US; 10Rev Ed edition, 2005.
MILK FERMENTATION




20-30% LESS LACTOSE




   Adolfsson O, Meydani SN, Russell RM. Yogurt and gut function. Am J Clin Nutr. 2004 Aug;80(2):245-56.
LACTOBACILLUS BULGARICUS & STREPTOCOCCUS
THERMOPHILUS EXPRESS FUNCTIONAL LACTASE




      YOGURT BETTER TOLERATED


     Adolfsson O, Meydani SN, Russell RM. Yogurt and gut function. Am J Clin Nutr. 2004 Aug;80(2):245-56.
BEER WILL CURE YOUR HYPOLACTASIA!!!
ADDITIONAL INFORMATION

 Established in 1904, University of Western States is located
  at
   2900 NE 132nd Avenue, Portland, Oregon, USA, 97230.
 Comprised of 50 quarter credits (550 hours, 33 semester
  credits), the UWS Master of Science degree program is
  accredited by Northwest Commission on Colleges and
  Universities.
 Course notes are copyrighted by University of Western
  States.
 Additional information is available at www.UWS.edu,
  Admissions@uws.edu, 503-251-5734, and
 http://www.uws.edu/Academic_Programs/MS_Nutrition_and_Functional_Medicine.aspx

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UWS Master's in Nutrition and Functional Medicine covers Milk, Dairy and Human Health

  • 1. UWS Master of Science in Nutrition and Functional Medicine  Course: Supplementation and Whole Food Nutrition  Week #: 4  Topic: Milk, Dairy and Human Health  Instructor: Pedro Carrera Bastos, MS
  • 2. OBJECTIVES FOR THIS WEEK  To understand the evolutionary pressures behind Adult lactase persistence  To recognize that Milk is a mammalian signaling system, with various hormonal effects  To know the current scientific evidence concerning Dairy, Metabolic Syndrome and Cancer  To understand the potential value of Dairy and/or its Proteins in Exercise Performance  To know the current evidence regarding Dairy and Body Composition  To understand the mechanisms behind Milk and Acne  To know the Casein A1/A2 controversy  To recognize the main differences between raw milk and pasteurized/homogenized milk  To understand the role of Calcium in Osteoporosis and Cardiovascular Disease  To recognize Milk Allergy  To understand the connection between Milk proteins and auto-immune diseases  To learn to prepare lactose/dairy-free, rich-calcium meals, and to know how to ferment milk
  • 3. TOPICS FOR THIS PRESENTATION Evolutionary History of Milk and Dairy Lactose Intolerance and ALP
  • 4. HISTORY OF MILK & DAIRY
  • 5. ORIGINS OF MAN Homo sapiens 0 H. heidelbergensis H. erectus Paranthropus H. neanderthalensis boisei 1 H. antecessor H. habilis P. robustus 2 H. ergaster Au. garhi Au. 3 rudolfensis P. aethiopicus Milhões de anos Kenyanthropus Au. africanus platyops Au. bahrelghazali 4 Ardipithecus ramidus Au. afarensis Au. anamensis 5 Orrorin tugenensis 6 7 Sahelanthropus tchadensis 8 Adapted from Wood B. Nature 2002:418:133-35 & from Cordain L, 2009
  • 6. All humans in Europe, Asia, Oceania and America have an AFRICAN ORIGIN Etiópia LESS GENETIC DIVERSITY Liu H, et al., 2006 OUTSIDE AFRICA Relethford JH. Heredity. 2008 Jun;100(6):555-63. Jakobsson M, et al. Nature 2008; 451(7181):998-1003 Manica A, et al. Nature; 2007; 448(7151):346-8 Hellenthal G, Auton A, Falush D. PLoS Genet. 2008 May 23;4(5):e1000078 Liu H, et al. Am J Hum Genet. 2006 Aug;79(2):230-7 Ramachandran S, et al. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15942-7 Conrad D, et al. Nat Genet 2006; 38: 1251–1260 Prugnolle F, Manica A, Balloux F. Current Biology 2005; 15:R159–R160 RAY N, et al. Genome Res 2005; 15:1161–1167 Cavalli-Sforza LL, Feldman MW. Nat Genet 2003; 33:266–275 Macaulay V, et al. Science 2005; 308(5724):1034-6 Tishkoff S, Williams S. Nat Rev Genet 2002; 3: 611–621 Currat M, Excoffier L. PLoS Biology 2004; 2: 2264–2274 Harpending, H, Rogers, AR. Annu Rev Genomics Hum Genet 2000; 1:361–385
  • 7. Liu H, et al. Am J Hum Genet. 2006 Aug;79(2):230-7
  • 8. WHAT WAS OUR ECOLOGICAL NICHE???
  • 9.
  • 10.
  • 11.
  • 12.
  • 13.
  • 15. VEGETABLE SOURCES  Plants  Roots & Tubers  Berries  Fruits  Nuts Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54
  • 16. ANIMAL SOURCES  Wild Animals  Insects  Seafood  Eggs Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54
  • 18. DAIRY REFINED SUGARS SALT LEGUMES CEREALS ALCOHOL FEEDLOT MEAT REFINED VEGETABLE OILS Cordain L. Implications of Plio-Pleistocene Hominin Diets for Modern Humans. In: Early Hominin Diets: The Known, the Unknown, and the Unknowable. Ungar, P (Ed.), Oxford University Press, Oxford, 2006, pp 363-83
  • 19. MILK? WHY NOT? Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54
  • 20. meses meses meses Sellen DW. J Nutr. 2001 Oct;131(10):2707-15
  • 21. BREASTFEEDING PATTERNS Sellen DW. J Nutr. 2001 Oct;131(10):2707-15
  • 22. ~11,000 YA Neolithic Revolution in the Middle East Cordain L et al. Am J Clin Nutr. 2005 Feb;81(2):341-54. Dubreuil L. Journal of Archaeological Science 2004; 31(11): 1613-1629. Bar-Yosef O. Evol Anthropol 1998;6:159 –77.
  • 23. EVIDENCE FOR THE USE OF DAIRY IN THE MIDDLE EAST First evidence of dairying in the Middle East (Turkey) 4 Domestication of sheeps, goats and cattle (Middle East) 1-3 Present 10,000 9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 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.
  • 24. GEOGRAPHIC EXPANSION OF THE FIRST NEOLITHIC CULTURES Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
  • 25. 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 Domestication of sheeps, goats and cattle (Middle East) 1-3 Present 10,000 9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 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
  • 26. UVB Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
  • 27. UVA Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
  • 28. FOLATE Miller AL, Kelley GS. Altern Med Rev. 1996;1(4):220-235
  • 29.  5MTHF absorbs UVB  oxidized to 5MDHF  5MDHF doesn’t re-enter the Folate pool  5MTHF is oxidized by ROS produced by naturally photosensitizers (flavins, porphyrins, bilirubin, etc.) after UVA exposure
  • 30. Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
  • 31. PIGMENTATION AND LATITUDE Chaplin G. Am J Phys Anthropol. 2004 Nov;125(3):292-302
  • 32.
  • 33. Liu H, et al. Am J Hum Genet. 2006 Aug;79(2):230-7
  • 34. Holick MF. J Clin Invest. 2006 Aug;116(8):2062-72
  • 35. Vitamin D deficiency 6 + months per year Vitamin D deficiency 1 + months per year Vitamin D all year Vitamin D deficiency 1 + months per year Vitamin D deficiency 6 + months per year Jablonski NG, Chaplin G. J Hum Evol. 2000 Jul;39(1):57-106
  • 36. Low Pigmentation 54 mJ/cm2 Pele muito pigmentada Pele muito 320 mJ/cm2 pigmentada Holick M. Am J Clin Nutr 2004;80(suppl):1678S– 88S.
  • 37. Low Pigmentation 54 mJ/cm2 High Pigmentation Pele muito 320 mJ/cm2 pigmentada Holick M. Am J Clin Nutr 2004;80(suppl):1678S– 88S.
  • 38. Low Pigmentation 54 mJ/cm2 High Pigmentation High 320 mJ/cm2 Pigmentation Holick M. Am J Clin Nutr 2004;80(suppl):1678S– 88S.
  • 39. FOOD SOURCES OF VITAMIN D Food Vit. D (IU) Cod Liver Oil (10 g) 1360 Sardins (105 g) 500 Tuna (105 g) 402 Farmed Salmon (105 g) 360 Egg (1 medium) 20 Liver (105 g) 15 Ozkan B. J Clin Res Pediatr Endocrinol. 2010 Dec;2(4):137-43
  • 40. Holick MF. J Clin Invest. 2006 Aug;116(8):2062-72
  • 41. Pelvic flattening, permanently narrowing the birth canal INCREASED MATERNAL MORTALITY DURING CHILDBIRTH Jablonski NG et al. J Hum Evol. 2000;39(1):57-106
  • 42. VDR IN MULTIPLE CELLS Holick MF. J Clin Invest. 2006 Aug;116(8):2062-72
  • 43. Zasloff M. Nat Med. 2006 Apr;12(4):388-90
  • 44. DEPIGMENTATION Darker Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B. Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
  • 45. UVA IS HIGHER IN THE POLES & SNOW REFLECTS UVA Jablonski NG, Chaplin G. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
  • 46.
  • 47. TF – Traditional Foods 1 mcg Vit D = 40 IU Kuhnlein HV, Receveur O. J Nutr. 2007 Apr;137(4):1110-4
  • 48. HIGH LATITUDE, CLOUDY CLIMATE, REDUCED SUNLIGHT N 65 DECREASED UV EXPOSURE & N 55 LESS VITAMIN D SYNTHESIS N 45 RICKETS Loomis WF. Science. 1967 Aug 4;157(788):501-6. Jablonski NG et al. J Hum Evol. 2000;39(1):57-106
  • 49. GEOGRAPHIC EXPANSION OF THE FIRST NEOLITHIC CULTURES Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
  • 50. THE SPREAD OF AGRICULTURE FROM THE MIDDLE EAST TO N. EUROPE BROUGHT NOT ONLY DAIRYING BUT ALSO WHEAT & BARLEY 5000 YA 6000 YA 8000 YA Jericho 10,000 YA 9000 YA Cordain, L., Hickey, M. S. & Kim, K. In press.
  • 51. The circum North/Baltic Seas land mass is warmed because of 1) Gulf Stream 2) Maritime nearness Mar do Mar Norte Báltico 55 N Average Temperature in Winter in London is 4 C vs - 9 C in N. America & Eurásia, at 51º N Seager R. The source of Europe’s mild climate. Am Sci 2006;94;334-41 . In Cordain, L., Hickey, M. S. & Kim, K. In press.
  • 52. Cordain L. World Rev Nutr Diet. 1999;84:19-73
  • 53.  High consumption (>50% energy) of whole grains (whole wheat, maize, oats, rye) are routinely used to induce rickets in dogs, rats, chickens and primates1-4  Epidemiological studies of human populations consuming high intakes of unleavened bread show rickets and vitamin D deficiency to be widespread 5-7 1Mellanby E. Lancet 1919;1:407-08. 2Thomas BH et al. Biochem J 1936;30:12-177-88 3Sly MR et al. Calcif Tissue Int 1984;36:370-79 4Grammer JC et al. Poult Sci 1983;62: 103-9 5Gibson RS et al. Brit J Nutr 1987;58:23-29 6Brooke OG et al. Brit J Obstet Gynaecol 1981;88:18-26 7Hunt SP et al. BMJ 1976;2:1351-54. In Cordain L. World Rev Nutr Diet. 1999;84:19-73
  • 54. HOW WHOLE GRAINS MAY PROMOTE RICKETS?  Increased elimination of vitamin D in bile1  Low Ca/P thereby promoting bone resorption2  Impaired labile calcium absorption via high phytate content3  Lectin (WGA) blockade of the nuclear pore, thereby preventing gene transcription of VDR4,5 1Batchelor AJ et al. Brit J Nutr 1983;49:213-16 2Cordain L. World Rev Nutr Diet. 1999; 84:19–73 3Mellanby E. J Physiol 1949;109:488-533 4Guinex C. et al. Int J Biochem Cell Biol 2005;37:765-74 5Findlay DR et al. J Cell Biol 1987;104:189-200
  • 55. WGA  Wheat Germ: 300 – 350 mg/kg WGA (1)  Whole Wheat Flour: 30-50 mg/kg WGA (2)  Refined Wheat Flour: 4.4 mg/kg WGA (2) 1. Vincenzi S, et al. J Agric Food Chem. 2002 Oct 23;50(22):6266-70. 2. Matucci A et al. Food Control 2004;15: 391-95
  • 56. Extreme Dermal Depigmentation originated in Northern Europeans ~ 5,300 – 6,000 years GEOGRAPHIC DISTRIBUTION FOR SKIN PIGMENTATION Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B. Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
  • 57. GEOGRAPHIC DISTRIBUTION FOR HAIR & EYE PIGMENTATION IN EUROPE Blond Hair / Blue Eyes originated in Europe ~ 6,000 – 10,000 YA Eiberg H et al. Hum Genet 2008;123:177-187. Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B. Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
  • 58.
  • 59. INCREASED CALCIUM INTAKE Pettifor JM. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1725S-9S
  • 60. Adapted from Cordain L, 2009 (with permission) 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.
  • 61. 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.
  • 62. BETA-CELLULIN Bastian SE, et al. Measurement of betacellulin levels in bovine serum, colostrum and milk. J Endocrinol. 2001 Jan;168(1):203-12.
  • 63. Adapted from Cordain L, 2009 (with permission) EGF in saliva: 0.0512 ng/ ml Total Saliva: 691 ml/24 hours EGF in 24h 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.
  • 64. Adapted from Cordain L, 2009 (with permission) WGA can bind luminally BTC expressed EGF-R or WGA Lumen EGF Receptor EGF Receptor To Lymph WGA Hormi K et al. Cell Tissue Res 1994;278:439-50 To Rebbaa A et al. J Neurochem 1996;67:2265-2272 Circulation Lochner N, et al. Pharm Res. 2003 May;20(5):833-9.
  • 65. LACTOSE SOURCES Food Serving (g) Lactose (g) Cow’s Milk 100 4.6 Buffalo Milk 100 5.1 Goat’s Milk 100 4.1 Sheep’s Milk 100 5.4 Park YW, Haenlein GFW. Handbook of Milk of Non-Bovine Mammals. Blackwell Publishing, 2006.
  • 66. LACTOSE HYDROLYSIS Lomer MC, Parkes GC, Sanderson JD. Aliment Pharmacol Ther. 2008 Jan15;27(2):93-103
  • 67. LACTOSE SOURCES Food Serving (g) Lactose (g) Human Milk 100 6.9 Cow’s Milk 100 4.6 Buffalo Milk 100 5.1 Goat’s Milk 100 4.1 Sheep’s Milk 100 5.4 LACTASE EXPRESSION IS COMMON IN MOST YOUNG MAMMALS Park YW, Haenlein GFW. Handbook of Milk of Non-Bovine Mammals. Blackwell Publishing, 2006.
  • 68. After the weaning period is over, lactase production usually declines , although the mechanisms and evolutionary reasons for this downregulation are not fully understood
  • 69. HIPOLACTASIA IS THE NORMAL PHENOTYPE IN HUNTER-GATHERERS AFTER AGE 3-5 Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
  • 70. Burger J, et al. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3736-41
  • 71. LACTOSE INTOLERANCE INTOLERÂNCIA À LACTOSE HIGH OSMOTIC HIGH OSMOTIC LOAD LOAD DIARRHEA DIARRHEA Lomer MC, Parkes GC, Sanderson JD. Aliment Pharmacol Ther. 2008 Jan15;27(2):93-103
  • 72. ALP IN EUROPE Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77. Predicted Old World LP phenotype frequencies based on -13,910 C>T allele frequency data only Estimated Dates of Origin: 2188 - 20650 BP (s = 0.014 - 0.150) 7450 - 12300 BP
  • 73. THE HIGHEST FREQUENCY OF THE -13,910 C>T allele IS CENTERED CONCENTRICALLY WITHIN ~ 1000 KM RADIUS OF THE NORTH & BALTIC SEAS (between 53º and 58º N) Baltic N. Sea (s = 0.090 - 0.190) Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B. Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
  • 74. The combination of 1) high latitude, 2) cloudy weather, 3) whole grain cereals as staples likely represented the unique combination of selective pressures responsible for the evolution of: ALP Blond Hair/Blue Iris Extreme Dermal Depigmentation (5,000 – 12,000 YA) (6,000 – 10,000 YA) (5,300 – 6,000 YA)  ALP: Ad libitum consumption of milk with GI distress protects against rickets by milk’s high calcium content1  Blond hair & blue eyes; extreme dermal depigmentation enhances dermal synthesis of vitamin D and further protects against rickets2 Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B. Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
  • 75. Domestication of the Arabian camel: 6000 BP Origin of G-13915 allele in the Arabian Pensinsula: 4000 BP Enattah NS, et al. Am J Hum Genet. 2008 Jan;82(1):57-72
  • 76. Spread of Pastoralism south of the Sahara: 4,500 BP Spread of Pastoralism into Northern Tanzania: 3,300 BP Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-40
  • 77. Various SNPs (G/C-14010, T/G- 13915 and C/G-13907) associated with LP in Sub-Saharan Africans arose 000 3000-7000 BP Tishkoff SA, et al. Nat Genet. 2007 Jan;39(1):31-40
  • 78. 20 N Equator 20 S  African children typically maintain normal plasma concentrations of vitamin D  High selection coefficient (s) for putative LCT alleles in sub-Saharan Africans (s = 0.035-0.097)  Is milk drinking protective of other pre-existing causes of mortality? Pfitzner MA et al. J Pediatrics 1998;133:740-4. In Cordain, L., Hickey, M. S. & Kim, K. In press.
  • 79. MALARIA INCIDENCE MALARIA MORBIDITY AND MORTALITY WORLD WIDE ARE HIGHEST IN SUB-SAHARAN AFRICA  ~75% of all cases of P. falciparum malaria and >80% of all malaria attributable deaths occur in sub-Saharan Africa Walther B et al. Ann Trop Med Parasitol 2007;101:657-72.
  • 80. GENETIC CHANGES IN GEOGRAPHIC AREAS WHERE MALARIA IS ENDEMIC  Hemoglobinopathies and other mutations influencing erythrocyte longevity  Sickle cell anemia  G6PD Deficiency  ALP in parts of Africa where animal Trypanosomiasis doesn’t occur Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B. Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
  • 81. Adapted from Cordain L, 2009 (with permission) MILK & MALARIA ???  All milk diets suppress malarial infections in birds, rodents and primates by restricting para amino benzoic acid (PABA) intake 1,2  The suppression of malarial symptoms is abrogated when supplemental PABA is added to all milk diets or PABA deficient diets of infected animals 2,3 1Kretschmar W et al. Tropenmed Parasit 1973;24:51-59 2Nowell F. Parasitology 1970;61:425-33. 3Kicska GA et al. Infect Dis 2003;188:1776-81
  • 82. Adapted from Cordain L, 2009 (with permission) PABA, FOLATE & MALARIA Pentose phosphate cycle Glycolysis  PABA synthase activity in Plasmodia is D-Erythrose 4-P Phosphoenolpyruvate low & poorly supports growth1  Dietary deficiencies of PABA & folate 7-Phospho-2-dehydro-3-deoxy-D-arabinoheptulosonate may suppress malarial symptoms by 3-Dehydroquinate synthase impairing folate metabolism1 3-Dehydroquinate 3-Dehydroquinate dehydratase  Dietary PABA and folate reduce 3-Dehydroshikimate efficacy of sulfa drugs in rodent Shikimate 5-Dehydrogenase models2 Shikimate Shikimate kinase Shikimate 3-Phosphate MILK DOES NOT CONTAIN PABA & IS 3-phosphoskikimate-1-carboxyvinyl transferase (EPSP synthase) A POOR SOURCE OF FOLATE 3-Phospho-5-enoylpyruvylshikimate (6-9 mg/100g vs. DRI 400 mg)3 Ubiquinone Chorismate Aromatic Amino Acids PABA synthase PABA Sulfonamides (additional PABA antagonizes sulfonamides) 1KicskaGA et al. Infect Dis 2003;188:1776-81 (inhibit plasmodial growth) Folate 2JacobsRL. Exp Parasitol 1964;15:213-25 3Johnston KE et al. J Food Sci 2002;67:817-20
  • 83.
  • 84. ALP & MALARIA  The pastoralist Fulani (>50 % ALP) exhibit resistance to malaria compared to other non-milk drinking African ethnic groups  Unexplained by genetic resistance factors, but rather by enhanced immunity  Displacement of PABA & Folate rich foods by milk may attenuate malaria infection while allowing immune exposure, thereby preventing serious symptoms & facilitate establishment of protective immunity Cordain, L., Hickey, M. S. & Kim, K. In press. Malaria and rickets represent selective forces for the convergent evolution of adult lactase persistence. In Biodiversity in agriculture: domestication, evolution and sustainability (eds P. Gepts, R. Bettinger, S. B. Brush, T. Famula, P. E. McGuire & C. O. Qualset). Cambridge, UK: Cambridge University Press.
  • 85. HIGH MILK INTAKE ASSOCIATED WITH HIGHER FOLATE RECEPTOR AUTOANTIBODIES Risk (OR [95% CI]) of FR-autoantibodies for each quintile compared with the lowest quintile of milk intake in men and women J. Nutr. 139: 1037–1041, 2009
  • 87. PREVALENCE OF ALP IN VARIOUS ETHNIC GROUPS 80 76 75 70 Percentage 60 50 40 30 27 25 20 20 10 10 3 0 Swallow DM. Ann Rev Genet 2003;37:197-219.
  • 88. PREVALENCE OF ALP IN VARIOUS EUROPEAN POPULATIONS 100 90 90 83 80 78 80 73 70 Percentage 70 65 60 58 60 55 52 52 50 50 40 40 38 40 35 30 26 26 25 20 15 10 10 0 GRADIENT NORTH WEST SOUTH EAST Swallow DM. Ann Rev Genet 2003;37:197-219.
  • 90. HIPOLACTASIA Occurs in ~ 65% of adults Gerbault P, et al. Philos Trans R Soc Lond B Biol Sci. 2011 Mar 27;366(1566):863-77.
  • 91. LACTOSE INTOLERANCE Abdominal Bloating (Small Bowell) Flatulence (Colon) Constipation HIGH OSMOTIC HIGH OSMOTIC LOAD LOAD DIARRHEA DIARRHEA Lomer MC, Parkes GC, Sanderson JD. Aliment Pharmacol Ther. 2008 Jan15;27(2):93-103
  • 92. DIAGNOSIS Lactose Milk Yogurt Mataix J. Nutrición y Alimentación Humana – Tomo I: Nutrientes y Alimentos. Ergon, 2002.
  • 93. LACTOSE FOOD SOURCES Food Serving Lactose (g) Cow’s Milk 1 glass 11 Ice-Cream 150 g 9-10 Cottage Cheese ~60 g 7-8 Parmesan ~60 g 1-2 Gouda ~60 g 1-2 Camembert ~60 g 0-1 GOOD TOLERANCE UP TO 12 GRAMS Pribila BA, et al. J Am Diet Assoc. 2000 May;100(5):524-8. Shils M.E. et al. Modern Nutrition in Health and Disease. Lippincott Williams & Wilkins, US; 10Rev Ed edition, 2005.
  • 94. MILK FERMENTATION 20-30% LESS LACTOSE Adolfsson O, Meydani SN, Russell RM. Yogurt and gut function. Am J Clin Nutr. 2004 Aug;80(2):245-56.
  • 95. LACTOBACILLUS BULGARICUS & STREPTOCOCCUS THERMOPHILUS EXPRESS FUNCTIONAL LACTASE YOGURT BETTER TOLERATED Adolfsson O, Meydani SN, Russell RM. Yogurt and gut function. Am J Clin Nutr. 2004 Aug;80(2):245-56.
  • 96. BEER WILL CURE YOUR HYPOLACTASIA!!!
  • 97.
  • 98. ADDITIONAL INFORMATION  Established in 1904, University of Western States is located at  2900 NE 132nd Avenue, Portland, Oregon, USA, 97230.  Comprised of 50 quarter credits (550 hours, 33 semester credits), the UWS Master of Science degree program is accredited by Northwest Commission on Colleges and Universities.  Course notes are copyrighted by University of Western States.  Additional information is available at www.UWS.edu, Admissions@uws.edu, 503-251-5734, and http://www.uws.edu/Academic_Programs/MS_Nutrition_and_Functional_Medicine.aspx

Editor's Notes

  1. Furthermore,infantswerebreastfeduntilabout 30 months
  2. Becausethe spread of AgriculturetoEuropetook time,
  3. Well,Exposure of 5MTHF to UVB results in oxidationto 5methyldihydrofolate,whichdoesn’t re-enter the Folate pool. Moreover, 5MTHF is oxidized by ROS produced by naturally photosensitizers (flavins, porphyrins, bilirubin, etc.) after UVA exposure.5MTHF is first oxidized to 5MDHF, and then the molecule is cleaved into PGA and an unknown pterin.
  4. Constantexposureto UVA and UVB radiationwill lead tolessFolateforCelldivision, compromisingReproduction and hencethesurvivalpfthespecies. Ifyoubelieve in Evolution, through natural selection, as I do, youwouldassumethatsuchanenvironmentalpressureisexpectedtoresult in geneticadaptations
  5. Indeed, thereis a stronginversecorrelationbetweenskinpigmentation and latitude
  6. We know that Hunter-Gatherers living below 30º latitude where in a UVB and UVA rich environment, allowing optimal cutaneous generation of vitamin D-3 from its precursor 7-dehydrocholesterol. But as further North they went, they could get Vitamin D deficiency during many months.Most studies of the effects of UV radiation on human skin have utilized as a standard the minimum-erythemal dose (UVMED), which is the quantity of UV radiation required to produce a barely perceptible reddening of lightly-pigmented skin
  7. Vitamin D deficiency significantly decreases Ca absorption, which decreases serum CaThis leads toincreasedParathyroid hormone releasefromtheparathyroidglandsParathyroid hormone increases Ca resorption in ordertomaintainstableserum Ca concentrationsPTH increaseshydrogenphosphateurinarylossThis leads toLesscalciumphosphateThis will lead to a Mineralization defectAnd hence Rickets
  8. Sunlight converts 7-dehydrocholesterol (7-DHC) in the skin to vitamin D3, which is converted successively to 25-hydroxy-D3 (25-D3) and then to 1,25-dihydroxy- D3 (1,25-D3) within keratinocytes. Sunlight also induces expression of the vitamin D receptor(VDR). 1,25-D3 and the VDR then together induce the expression of the gene encoding the human antimicrobial peptide LL-37. Vitamin D3 enters the systemic circulation and is converted to 25-D3 by the liver. Circulating monocytes are activated by TLR2/1 agonists present on specific microbes. The genes encoding VDR and CYP 27B1 are induced. CYP27B1 converts 25-D3 from the circulation to 1,25-D3, joins with the VDR and activates the gene encoding LL-37, leading to an increase in cellular LL-37 and enhanced microbicidal activity of the phagocyte.
  9. Thesolutiontothisproblemwasskindepigmentation
  10. Bu what about the Inuit people? They live at high latitudes, so why they do not have light pigmented skin???
  11. Normally at high latitudes extreme temperatures cause the growing season to be too short for plant foods to compete with animal foods as staplesThe circum North/Baltic Seas land mass is warmed because of Gulf Stream 2) Maritime nearnessFor instance, AverageTemperatureinWinterinLondonis4°Cvs- 9 °C in N. America & Eurásia, at51º N
  12. Hence, this 1000 km radius of surrounding land was the furthest North that cereals could be grown prior to modern agriculture
  13. Whole Wheat Flour contains30-50 mg/kg WGA, so a Neolithic Farmer would be consuming 15-25 mg/dayof WGA
  14. A geneticadaptationtoincraesedrickets in NorthernEuropewasExtremeDermal Depigmentation about5,300 – 6,000 years
  15. Another adaptation was hair depigmentation and lowconcentrations of melanin in the stroma of the iris, whichgivestheblueeyeappearanceundercertainexternallightingconditions. Againthishappen in Europeabout6,000 – 10,000 YA Quanto+ claraé a corcastanha, maisclaroé o cabelo e olhos
  16. Anothersolutiontoavoidricketswould be increasing Ca intake. SinceMilkcontains 300 mg of Ca per 225 ml, itwould be thelogicalchoice.
  17. lactase-phlorizin hydrolase in the brush border efficiently hydrolyses lactose into galactose (Gal) and glucose (Glu) and is rapidly absorbed into the bloodstream taking luminal water with it. Hydrolysis typically occurs in the jejunum, which has low concentrations of bacteria 101-4 mL-1; thus, little lactose is fermented.
  18. Indeed, thearchaeological dates for the spread of domesticated animals and dairying into Europe fit into the date estimate for the emergence of the SNP in the gene encoding lactase, which is associated with adults lactase persistence in Europeans. The selection coefficient (s) for this allele in Europeans is 0.014 - 0.150
  19. The selection coefficient (s) for this allele in Scandinavians is = 0.090 - 0.190Which has been labeled: 1) “among the strongest yet seen for any gene in the genome”“one of the strongest genetic signatures of natural selection yet reported in humans”The frequency of this allele is much higher in Northern Europe than anywhere else. And, just like skin depigmentation, light hair and blue eyes it is centered concentrically within ~ 1000 km radius of the North & Baltic Seas
  20. Andcoming back totheMiddle East again, wehavethedomestication oftheArabiancamelabout 6,000 years ago. Thisfitsinto the date estimate (about 4,000 years ago) for the emergence of anotheralleleassociatedwithadult lactase persistence. Thisalleleisfound in highfrequencyamong a fewpastoralistgroupssuch as SaudiArabians and Bedouins of Sinai, amongwhichtheArabiancamel has beenthemaindomesticated animal usedformilk
  21. In Africa, the Spread of Pastoralism south of the Sahara occurred about 4,500 years ago and into Northern Tanzania happened about 3,300 years ago.
  22. In accordance with this, the date estimate for at least 3 SNPsassociatedwithlactase persistence in Sub-SaharanAfricansis3000-7000 years ago.
  23. CompromisedUV exposure would not have been a selective pressure for the evolution of ALPin sub-Saharan Africans, since African children typically maintain normalplasma concentrations of vitamin DNevertheless, the high selection coefficient (s) for putative LCT alleles in sub-Saharan Africans (s = 0.035-0.097), which is suggestive that milk drinking is highly protective of other pre-existing causes of mortality
  24. Indeed, in geographic areas where Malaria is Endemic there were genetic changes that resulted in Sickle cell anemia,Glucose-6-phosphate dehydrogenase Deficiency and other Hemoglobinopathies & conditions influencing erythrocyte longevity.Another genetic change believed to be driven by Malaria was ALP in certain parts of Africa. Why it didn’t happen all over sub-Saharan Africa?Because Selection for ALP may have been prevented by animal trypanosomiasiswhich precludes widespread cattle husbandry in much of Africa.Anemia falciforme (ou drepanocitose) é o nome dado a uma doença hereditária que causa a malformação das hemácias, que assumem forma semelhante a foices (de onde vem o nome da doença), com maior ou menor severidade de acordo com o caso, o que causa deficiência do transporte de oxigênio nos indivíduos acometidos pela doença. – resulta de uma mutação no gene da hemoglobinaG6PDH) is a cytosolicnzyme in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (such as erythrocytes) by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage
  25. Because PABA, pterin and glutamate moieties are required for the de novo synthesis of folate in bacteria (including Plasmodia sp.)1