Circadian Rhythm and Malignancy

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Circadian Rhythm and Malignancy

  1. 1. Circadian Rhythm andits Role in Malignancy Andrew S. Bonci, BA, DC MSCA D-II February 2011 www.drbonci.com 1
  2. 2. Where in the World is all of the Cancer? www.drbonci.com 2
  3. 3. Disclosures ● I work for NO special interest or lobbying groups nor do I receive stipends, consulting fees, gratuities or honoraria from any pharmaceutical or nutritional companies. ● I am NOT a fan of Big Pharma or sell-out government officials and this may show.www.drbonci.com 3
  4. 4. Objectives● Understand the Impact of Light-Dark Cycles on Health and Disease.● Discuss Circadian Rhythms in Light of Malignancy.● Offer the Practicing Chiropractor Practical Tools to Help Prevent and Co-Manage the Phenomenon called Cancer . www.drbonci.com 4
  5. 5. “As a nation, we are sickbecause we dont sleep.We are fat and diabeticbecause we dont sleep.We are dying from cancer andheart disease because wedont sleep.” T. S. Wiley & B. Formby Lights Out: Sleep, Sugar, and Survival (2000) www.drbonci.com 5
  6. 6. Death by Endless Summer(Artificially long days) +(Endless brain bath ofCortisol + Dopamine) +(Food Abundance) +(Sleep Deprivation) =Death by EndlessSummer www.drbonci.com 6
  7. 7. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 7
  8. 8. Jiddu Krishnamurti (1895 – 1986) “It is no measure of health to be well adjusted to a profoundly sick society.” www.drbonci.com 8
  9. 9. A Profoundly Sick Society www.drbonci.com 9
  10. 10. A Profoundly Sick Society www.drbonci.com 10
  11. 11. A Profoundly Sick Society www.drbonci.com 11
  12. 12. A Profoundly Sick Society www.drbonci.com 12
  13. 13. A Profoundly Sick Society www.drbonci.com 13
  14. 14. A Profoundly Sick Society www.drbonci.com 14
  15. 15. A Profoundly Sick Society www.drbonci.com 15
  16. 16. A Profoundly Sick Society www.drbonci.com 16
  17. 17. A Profoundly Sick Society www.drbonci.com 17
  18. 18. A Profoundly Sick Society www.drbonci.com 18
  19. 19. A Profoundly Sick Society www.drbonci.com 19
  20. 20. AProfoundlySickSocietyWPA Posters (Works ProgressAdministration) were made duringthe WWII Era between 1936 and1943 as part of Franklin DelanoRoosevelts New Deal.
  21. 21. ● Dr. David R. HawkinsMans dilemma– now andalways – hasbeen that hemisidentifies hisown intellectualartifacts asreality.
  22. 22. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 22
  23. 23. Joseph Campbell “This thing up here, this consciousness, thinks its running the shop. Its a secondary organ. Its a secondary organ of a total human being, and it must not put itself in control. It must submit and serve the humanity of the body.” The Power of Myth (1988)
  24. 24. BJ Palmer"But when education becomesegotistical and paramount anddisplaces the correct values ofInnate, all else becomes"uneducated", sub-conscious,non-conscious, and un-conscious.Education then becomes animpenetrable wall Innate doesnot and cannot break through." The Bigness of the Fellow Within. p. 18. Video Follows
  25. 25. Were Losing the War on Cancer David Angus from www.TED.com www.drbonci.com 25
  26. 26. Why do wethink aboutcancer theway that wedo? Are WeFocused on the Right Things? www.drbonci.com
  27. 27. Chemical Warfare Circa 1915 French troops used xylylbromide against German troops. The Germans retaliated against the French by lobbing chlorine gas. Mustard gas proved more insidious. This gas was odorless and could be be taken deeply into the lungs. lungs Davis. The Secret History of the War on Cancer. 2007. p. 199-200. www.drbonci.com
  28. 28. Chemical WarfareThose who were not killed in a few hours wereleft with telltale blisters and scars on whateversurfaces that the gas had touched.Their survival providedsome fundamentallessons about howthe human bodyresponds tochemicals. Davis. The Secret History of the War on Cancer. 2007. p. 199-200. www.drbonci.com
  29. 29. WBC Observations Circa 1919A U.S. Army captain named E.B. Krumbhaaridentified a pattern in the blood of the men who hadbeen gassed. gassed The white blood cell counts of these gassed survivors were amazingly low. low Some of these men developed lung cancer. cancer The conclusion: mustard gas lowers white blood cell counts. Davis. The Secret History of the War on Cancer. 2007. p. 201. www.drbonci.com
  30. 30. LeukemiaSome physicians (Virchow)in the 1800s published casereports on patients with waytoo many white blood cells.Patients with leukemia canhave white cell counts ashigh as several hundredthousand.thousandRecall that, survivors of poison gas attacks duringWWI, often had close to zero WBC counts. counts Davis. The Secret History of the War on Cancer. 2007. p. 201. www.drbonci.com
  31. 31. Thomas Dougherty, PhD Circa 1930 The Yale anatomist asked a question that was both fundamental and simple: “Could poison gas be altered so that it could kill cancer without killing the patient?” This was the beginning of Chemical Warfare directed against pathologies. Davis. The Secret History of the War on Cancer. 2007. p. 201. www.drbonci.com
  32. 32. Goodman and GilmanTwo Yale assistant professors applied the idea ofDougherty in the 1930s and 1940s first on rats,then on humans. humansThey reported in a 1946 issue of JAMA that theintravenous infusion of nitrogen mustard kept afew terminal cancer patients alive.The treatment worked best for patients withHodgkins lymphoma. lymphomaMany patients died soon after the infusionsbegan. Davis. The Secret History of the War on Cancer. 2007. p. 202. www.drbonci.com
  33. 33. Leukemia is Often Complicated by Red Cell AnemiasSince leukemia was notamenable surgically, thisinstigated a search forfactors that could: 1.Kill White Blood Cells (vide supra) 2.Cure the Red Cell Anemia (vide infra) www.drbonci.com
  34. 34. Dr. George Minot Circa 1926 Discovered Vitamin B12 while trying to find a cure for pernicious anemia. Fed patients mulched chicken livers and the gastric contents of his assistant. In 1934 he was awarded the Nobel Prize along with two of his colleagues. Siddhartha Mukherjee. The Emperor of all Maladies, 2010. www.drbonci.com
  35. 35. Dr. Lucy Wills Circa 1929Working to cure amacrocytic anemia inIndia, she found that B12didnt always work.Discovered a factor inMarmite (Vegimite) whichshe called Wills Factor(folate) resolved thisvariant of macrocyticanemia.Siddhartha Mukherjee. The Emperor of all Maladies, 2010. www.drbonci.com
  36. 36. Dr. Sidney Farber Circa 1946 A pediatric pathologist working in Boston, became interested in the anemia associated with leukemia. Applied the findings of Lucy Wills. He infused synthetic folic acid which he obtained from a colleague into a group of leukemic children. It accelerated their disease and killed them in a matter of days to weeks.This was reported in a 1948 article in NEJM that children withleukemia were found to die more quickly when given folic acid. acid Davis. The Secret History of the www.drbonci.com War on Cancer. 2007. p. 204.
  37. 37. Dr. Sidney Farber Circa 1948Given the previous disaster, Farberreasoned that an antifolate wouldcure the children of leukemia.When these children were givenagents that blocked the utilization offolic acid (aminopterin), their tumorswere extinguished albeit temporarily. A boon for pharmacology and a blow to nutrition. Davis. The Secret History of the War on Cancer. 2007. p. 204. www.drbonci.com
  38. 38. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 38
  39. 39. A Brief Overview of ThePhenomenon Called Cancer www.drbonci.com 39
  40. 40. Defining Cancer Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. http://www.cancer.gov/cancertopics/what-is- cancer www.drbonci.com 40
  41. 41. Cancer is a Preventable DiseaseOnly 5-10% of all cancer cases can be attributedto genetic defects, whereas the remaining 90-95% have their roots in the environment andlifestyle.Common environmental factors that lead tocancer death include: tobacco (25-30%), dietand obesity (30-35%), infections (15-20%),radiation, stress, lack of physical activity, andenvironmental pollutants.Pharm Res. 2008 Sep;25(9):2097-116. www.drbonci.com 41
  42. 42. Cause of Cancer Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. N Engl J Med. 2008 Jan 31;358(5):502-11. www.drbonci.com 42
  43. 43. HmmmmmmmmmmIf cancer is a problemof cell growth andregulation, then what isrequired to help a cellremain a fullyfunctioning, normal,healthy cell?How does one avoiddysplasia or amaturation abnormality? www.drbonci.com 43
  44. 44. Cellular AbnormailitesDysplasia, a maturational abnormality, is oftenindicative of an early neoplastic process. Metaplasia is the reversible replacement of one differentiated cell type with another mature differentiated cell type. www.drbonci.com 44
  45. 45. AnaplasiaThe term anaplasialiterally means "toform backward".It impliesdedifferentiation, orloss of structuraland functionaldifferentiation ofnormal cells. www.drbonci.com 45
  46. 46. Cancer is a Cellular AdaptationCancers have been shown to be clonallyderived from a single cell, and so it does seemthat stem cells are target cells for carcinogenesis.The hypothesis … explicitly states that cancer isthe adaptation of the aged/adult stem cellagainst sustained stress.Rejuvenation Res. 2008 Dec; 11(6): 1059-60. www.drbonci.com 46
  47. 47. Adult/Somatic/Aged Stem CellsAdult stem cells areundifferentiated cells,found throughout thebody after embryonicdevelopment, thatreplenish dying cellsand regeneratedamaged tissues.www.wikipedia.org/wiki/Adult_stem_cell www.drbonci.com 47
  48. 48. Circadian Rhythms Control Adult Stem Cell Activites Hemopoietic stem cell traffic and hematopoiesis do not escape the circadian regulation that controls most physiological processes. Current Opinion in Hematology July 2009; 16(4): 235-242 www.drbonci.com 48
  49. 49. Cancer Derived Cell Models There is a wealth of in vivo and in vitro evidence implicating the CCRP (core circadian regulatory proteins) in the growth of tumors and, by extension, cancer stem/progenitor cells. J Cell Biochem. 2009 Jul 1;107(4):569-78. www.drbonci.com 49
  50. 50. Cancer Derived Cell ModelsThe Period genes havebeen associated with anumber of tumors,including myeloidleukemia, breast, andlung cancers.J Cell Biochem. 2009 Jul 1;107(4):569-78. www.drbonci.com 50
  51. 51. Circadian Expression of Clock and Tumor Suppressor Genes Circadian rhythms are daily oscillations of multiple biological processes driven by endogenous clocks. Imbalance of these rhythms has been associated with cancerogenesis in humans. Cell Physiol Biochem. 2010;26(2):155-66. www.drbonci.com 51
  52. 52. Circadian Clock & CarcinogenesisCircadian clock geneexpression is changed inhuman pathologiesincluding cancers.The circadian clockregulates the activity ofcell cycle check-point-related proteins andvice versa.Ann Med 2010 Sep; vol. 42(6) pp. 404-15. www.drbonci.com 52
  53. 53. Father William of Ockham“Pluralitas non est ponenda sine necessitate.” Plurality is not to be posited without necessity. For Ockham, the only truly necessary entity is God. www.drbonci.com 53
  54. 54. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 54
  55. 55. Cancer Statistics in Brief www.drbonci.com 55
  56. 56. Video Follows
  57. 57. The Realization that Living Outside of Normal Time Rhythms has a Devastating Effect www.drbonci.com 61
  58. 58. Shift-Work is Carcinogenic(Reuters) - Shift workersand firefighters have ahigher risk of cancerthan the general populationand such work should beclassified as probably orpossibly carcinogenic,the International Agency forResearch on Cancer said onFriday. By Maggie Fox, Health and Science Editor WASHINGTON | Fri Nov 30, 2007 1:57pm EST http://www.reuters.com/article/idUSN3029736520071130
  59. 59. Light-at-Night DisruptionWe conclude that circadian disruption induced bylight-at-night accelerates aging and promotestumorigenesis in rats. This observation supports the conclusion of the International Agency Research on Cancer that shift-work that involves circadian disruption is probably carcinogenic to humans. Aging (Albany NY). 2009 Oct 2;1(10):855-65.
  60. 60. Chronodisruption and Cancer.[M]eta-analyses of 30epidemiological studies[demonstrate] that shiftworkers exposed tochronodisruption mayhave increased breast andprostate cancer risks: ● 40% increase in the risk of breast cancer and prostate cancer Naturwissenschaften. 2008 May;95(5):367-82.
  61. 61. Circadian Disruption, Shift Work and the Risk of Breast Cancer Epidemiologic studies are now beginning to emerge suggesting that women who work at night, and who experience sleep deprivation, circadian disruption, and exposure to light-at-night are at an increased risk of breast cancer, and possibly colorectal cancer as well. Cancer Causes Control. 2006 May;17(4):539-45.
  62. 62. Risk of Prostate Cancer Among Rotating-Shift WorkersCompared with dayworkers, rotating-shiftworkers weresignificantly at risk forprostate cancer(relative risk = 3.0, 95%confidence interval: 1.2,7.7).Am. J. Epidemiol. (15 September 2006) 164 (6): 549-555.
  63. 63. One in Five Americans Approximately 15.2 million Americans work full-time evenings, nights, irregular schedules dictated by their employers, and rotating shifts, in which they shift from days to evenings, typically on a weekly basis. US Bureau of Labor Statistics & Smolensky (2000) www.drbonci.com
  64. 64. Chronodisruption Kills ● The crisis at Three Mile Island nuclear power plant started between 4 and 6 AM on March 28, 1979. ● The chemical disaster in Bhopal, India occurred at 12:40 AM on December 4, 1984. ● Chernobyl nuclear power plant exploded on April 26, 1986 at 1:23 AM. ● The Exxon Valdez ran aground at 12:04 AM on March 24, 1989.Smolensky. The Body Clock. 2000; p.167-8 www.drbonci.com
  65. 65. Shift-Work/Chronodisruption● Awake at Night ● Dysregulation of Melatonin Release● Asleep During Daylight ● Dysregulation of Vitamin D Production
  66. 66. Robert Burton (1577-1640) “Our body is like a clock; if one wheel is a miss, all the rest are disordered, the whole fabric suffers: with such admirable art and harmony is a man composed.” Robert Burton, 1577-1640 English Scholar/Author Anatomy of Melancholy www.drbonci.com
  67. 67. Melatonin, Sleep Disturbance and Cancer Risk.The pineal hormonemelatonin is involved inthe circadian regulationand facilitation of sleep,the inhibition ofcancer developmentand growth, and theenhancement ofimmune function.Sleep Med Rev. 2009 Aug;13(4):257-64.
  68. 68. Occupational Sunlight Exposure and Risk of Cancer Recent findings indicate that vitamin D obtained from ultraviolet (UV) exposure may reduce the risk of several different cancers. Cancer. 2010 Apr 15;116(8):2001-10.
  69. 69. Melatonin and Vitamin D3Melatonin and vitamin D3inhibit breast cancer cellgrowth and induce apoptosis.In breast cancer cells,melatonin together withvitamin D3, induced asynergistic proliferativeinhibition, with an almostcomplete cell growth arrest.J Pineal Res. 2010 Nov 22.
  70. 70. No Sun Worshiper Here Sunlight serves a critical function: it synchronizes the biological clock with planetary time. Synchronizing, also called entraining, establishes predictability and promotes survival. Smolensky. The body Clock. 2000; p.25 www.drbonci.com
  71. 71. Light-Dark Hormonal Signals Melatonin is the hormone of darkness Vitamin D is the hormone of light
  72. 72. A Primordial Planetary Axis Melatonin Non-Steroid Hormone Produced in response toCholecalciferol darknessSteroid HormoneProduced inresponse to light
  73. 73. Single Axis Hormonal Regulation Sophisticated systems of feedback requiring one hormone and a central nervous system. This is a more recent evolutionary development. This is the HPA axis. www.drbonci.com 77
  74. 74. Dual Axis Hormonal RegulationThis system of hormonalregulation andhomeostatic balancerequires twocompetitively actinghormones.This is a more archaicsystem. www.drbonci.com 78
  75. 75. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 79
  76. 76. What is Melatonin? Melatonin also known chemically as N-acetyl- 5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes. http://en.wikipedia.org/wiki/Melatonin www.drbonci.com 80
  77. 77. Serotonin-Melatonin Pathway www.drbonci.com 81
  78. 78. Endocrine Melatonin Melatonin produced in the pineal gland, which is outside of the blood- brain barrier, acts as an endocrine hormone since it is released into the blood. http://en.wikipedia.org/wiki/Melatonin www.drbonci.com 82
  79. 79. Paracrine MelatoninBy contrast, melatoninproduced by the retinaand the gastrointestinal(GI) tract acts as aparacrine hormone.http://en.wikipedia.org/wiki/Melatonin www.drbonci.com 83
  80. 80. Site of ActionG protein-coupled [Melatonin] has beenreceptor found to interact with protein receptors both at the cell membrane and in the nucleus. [M]elatonin was recently shown to be a very potent hydroxyl radical scavenger. J Pineal Res. 1995 Oct;19(3):123-6. www.drbonci.com 84
  81. 81. Melatonin is MelatoninThe melatonincirculating in your veinsis chemically thesame as that extractedfrom algae, plants,insects, frogs, and seals.RJ Reiter and J Robinson. Melatonin. 1995. www.drbonci.com 85
  82. 82. Melatonin in Plants Melatonin in plants has multiple roles including regulation of the photoperiod, in plant defense responses, and as a scavenger of reactive oxygen species. Journal of Experimental Botany 2009; 60 (1): 57–69. www.drbonci.com 86
  83. 83. Melatonin in Animals [Melatonin] serves as a biological signal for the organization of photoperiodic seasonal functions such as reproduction, behavior, coat growth and camouflage coloring in seasonal animals. Sleep Med Rev. 2005 Feb;9(1):25-39. www.drbonci.com 87
  84. 84. Melatonin Toxicity Melatonin has a very low toxicity in rats. Rat maternal toxicity: the no observable adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was >= 200 mg/kg/day. Toxicological Sciences 1999;50(2):271-9. www.drbonci.com 88
  85. 85. Anti-Cancer Effects of Melatonin● antioxidant effects ● inhibition of telomerase activity● regulation of the estrogen receptor ● inhibition of metastasis expression ● prevention of circadian● modulation of the disruption enzymes involved in the ● antiangiogenesis local synthesis of stimulation of cell estrogens differentiation● modulation of cell cycle ● activation of the immune and induction of system. apoptosis Curr Med Chem. 2010 Nov 10. www.drbonci.com 89
  86. 86. Melatonin as AntioxidantMelatonin can easilycross cell membranes andthe blood-brain barrier.Endocrine. 2005 Jul;27(2):119-30.Is a suicidal or terminalantioxidant whichdistinguishes it from theopportunistic antioxidants.Biol Signals Recept. 2000 May-Aug;9(3-4):137-59. www.drbonci.com 90
  87. 87. An Established Antioxidant Worthy of Use in Clinical Trials Accumulating evidence suggests that this nontoxic indolamine may be useful either as a sole treatment or in conjunction with other treatments for inhibiting the biohazardous actions of nitrooxidative stress. Mol Med. 2009 Jan-Feb;15(1-2):43-50. www.drbonci.com 91
  88. 88. Melatonin Estrogen ReceptorMelatonin has beenshown to inhibit theproliferation ofestrogen receptor α(ERα)-positive humanbreast cancer cells invitro and suppress thegrowth of carcinogen-induced mammarytumors in rats.J Pineal Res. 2010 Oct;49(3):210-21. www.drbonci.com 92
  89. 89. Melatonin & AromataseMelatonin inhibits aromatase promoterexpression by regulating cyclooxygenaseexpression and activity in breast cancer cells.Br J Cancer. 2009 Nov 3;101(9):1613-9. www.drbonci.com 93
  90. 90. Melatonin Regulates ApoptosisMelatonin treatment substantially preventsCCl(4)-induced apoptosis and oxidative damage inthe liver.Toxicol Ind Health. 2008 May;24(4):201-8. www.drbonci.com 94
  91. 91. Melatonin & Telomerase Activity Melatonin exhibits oncostatic properties. Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro. Telomerase is an enzyme responsible of telomere elongation and is activated in“Vitamin D slows the most human cancers.rate of telomere J Pineal Res. 2003 Oct;35(3):204-11.shortening.”www.telomerase.org www.drbonci.com 95
  92. 92. MMP, ICAM & MelatoninMelatonin inhibitsMatrixMetalloproteinaseactivity while stabilizingintercellular adhesionmolecules.J Pineal Res. 2010 Oct 22. www.drbonci.com 96
  93. 93. Melatonin Suppresses Tumor Angiogenesis. J Pineal Res. 2010 Mar;48(2):178-84. www.drbonci.com 97
  94. 94. Melatonin & ImmunityMelatonin stimulates theproduction ofprogenitor cells forgranulocytes andmacrophages.It also stimulates theproduction of naturalkiller cells and CD4+cells and inhibits CD8+cells.Neuroimmunomodulation. 2008;15(4-6):272-8. www.drbonci.com 98
  95. 95. NSAIDS Effect on Melatonin Nonsteroidal anti-inflammatory drugs alter body temperature and suppress melatonin in humans. Physiol Behav. 1996 Jan;59(1):133-9. www.drbonci.com 99
  96. 96. NSAIDS Disrupt SleepSleep disruption afterNSAID administrationmay relate to decreasesin prostaglandin D2,suppression of nighttimemelatonin levels, andchanges in bodytemperature.Physiol Behav. 1994 Jun;55(6):1063-6. www.drbonci.com 100
  97. 97. Beta Blockers Block Melatonin Beta-blockers decrease melatonin release via specific inhibition of adrenergic beta1-receptors. Eur J Clin Pharmacol. 1999 Apr;55(2):111-5. www.drbonci.com 101
  98. 98. Caffeine Lowers MelatoninMelatonin secretion iscontrolled byneurotransmitters thatcan be affected bycaffeine.Consumption of caffeinedecreases 6-sulphoxymelatoninexcretion.Sleep Med. 2002 May;3(3):271-3. www.drbonci.com 102
  99. 99. Agomelatine: New Drug. Agomelatine, a melatonin receptor agonist, is approved in the European Union for the treatment of depression. In summary, agomelatine has unproven efficacy and poorly documented adverse effects. Prescrire Int. 2009 Dec;18(104):241-5.“The First Melatonergic Antidepressant” www.drbonci.com 103
  100. 100. ROZEREM (rō-Zair-em) (ramelteon) Another Melatonin Receptor Agonisthttp://www.rozerem.com www.drbonci.com 104
  101. 101. Pharmakos (Greek: φαρμακός)The term "pharmakos"later became the term"pharmakeus" which refersto "a drug, spell-givingpotion, druggist, poisoner,by extension a magician ora sorcerer."Jim Lynn, The Miracle of Healing in Your Church Today. p.93 “Scapegoat” www.drbonci.com 105
  102. 102. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 106
  103. 103. What is Vitamin D?Vitamin D (calciferol) comprisesa group of fat soluble seco-sterols found naturally only ina few foods, such as fish-liveroils, fatty fish, mushrooms, eggyolks, and liver.The two major physiologicallyrelevant forms of vitamin D areD2 (ergocalciferol) and D3(cholecalciferol). www.drbonci.com 107
  104. 104. Where is Vitamin D Synthesized? Vitamin D from the skin or diet is only short-lived in circulation (with a half-life of 1–2 days), as it is either stored in fat cells or metabolized in the liver (Mawer 1972). In circulation, vitamin D is bound to vitamin D-binding protein and transported to the liver, where it is converted to 25-hydroxyvitamin D [25(OH)D] (DeLuca 1984). www.drbonci.com 108
  105. 105. Vitamin D is a HormoneActive vitamin D functions as a hormone, and its main biologicfunction in people is to maintain serum calcium and phosphorusconcentrations within the normal range by enhancing the efficiency ofthe small intestine to absorb these minerals from the diet (DeLuca1988; Reichel 1989). www.drbonci.com 109
  106. 106. Canonical Vitamin D 1.Skin-Liver- Kidney Activation 2.Endocrine Function 3.Enteric Calcium Binding Protein 4.Enteric Calcium Channel www.drbonci.com 110
  107. 107. Non-Canonical Vitamin D1.Peripheral Tissue Activation2.Paracrine Function3.Human Proton- Coupled Folate Transporter www.drbonci.com 111
  108. 108. Vitamin D Improves Folate Status Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol. 2009 Nov;76(5):1062-71. www.drbonci.com 112
  109. 109. Folic Acid, Folate or Vitamin B9Folic acid (also known asvitamin B9 or folacin) andfolate (the naturallyoccurring form), as wellas pteroyl-L-glutamic acid,pteroyl-L-glutamate, andpteroylmonoglutamic acidare forms of the water-soluble vitamin B9.http://en.wikipedia.org/wiki/Folic_acid www.drbonci.com 113
  110. 110. Role of Folate Folate is necessary for the production and maintenance of new cells, for DNA synthesis and RNA synthesis, and for preventing changes to DNA, and, thus, for preventing cancer. Semin Oncol. 1997 Oct;24(5 Suppl 18):S18-30- S18-39. www.drbonci.com 114
  111. 111. Vitamin D-Folate-MelatoninJ Nutr. 2002 Sep;132(9):2781-4. www.drbonci.com 115
  112. 112. Betaine/Betaine-Homocysteine MethyltransferaseThe original betaine (bee ta een), N,N,N-trimethylglycine, was named after its discovery insugar beets (Beta vulgaris) in the 19th century.Intracellular accumulation of betaineprotects protein structure andmembrane integrity while preventingcellular dehydration.It is also a methyl donor ofincreasing significance.http://en.wikipedia.org/wiki/Betaine www.drbonci.com 116
  113. 113. S-Adenosyl MethionineA common co-substrate involved in methylgroup transfers.The methyl group (CH3) attached to themethionine sulfur atom in SAM is chemicallyreactive.http://en.wikipedia.org/wiki/SAM-e www.drbonci.com 117
  114. 114. HIOMT/Hydroxylindole-O-MethyltransferaseHIOMT mRNA displays a day/nightvariation,with a 2-fold increase in nighttimelevels.This day/night variation persists underconstant darkness and is abolished bylight applied at night, indicating thatHIOMT gene expression iscontrolled by the endogenous clock.Endocrinology. 1999 Mar;140(3):1375-84. www.drbonci.com 118
  115. 115. Vitamin D-Folate-Melatonin Connection ● During the Light Cycle ● Vitamin D levels increase ● Folate absorption Increases ● Melatonin Precursors Assemble ● During the Dark Cycle ● Melatonin is released www.drbonci.com 119
  116. 116. Sunlight & Season on SerotoninSummer sunlightincreases brainserotonin levels twice asmuch as wintersunlight, a findingcompatible with bothbright light in the visiblespectrum and vitaminD affecting mood.Lancet. 2002 Dec 7;360(9348):1840-2. www.drbonci.com 120
  117. 117. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 121
  118. 118. Vitamin D and Cancer Video Follows www.drbonci.com
  119. 119. The GiftStacey Kramer from www.TED.com www.drbonci.com 123
  120. 120. Vibe is a 7 years old girl from Denmark who was diagnosed with an inoperable tumor in 2007. Vibe has received 30 radiation treatments, four chemotherapy treatments, and three high dosage chemotherapy treatments.http://bop.nppa.org/2009/still_photography/winners/?cat=UPS&place=3rd&item=140479 www.drbonci.com 124
  121. 121. In January 2009,Vibe lost the fightagainst cancer.At the time of herdeath she wasseven years old.http://www.bitemagazine.net/2010/08/24/a-family-life-between-hospitalizations-and-chemotherapy/ www.drbonci.com 125
  122. 122. It is projected that raising the minimum year-around serum 25(OH)D levelto 40 to 60 ng/mL would prevent approximately 58,000 new cases ofbreast cancer and 49,000 new cases of colorectal cancer each year, andthree fourths of deaths from these diseases in the United States andCanada, based on observational studies combined with a randomizedtrial.Such intakes also are expected to reduce case-fatality rates of patientswho have breast, colorectal, or prostate cancer by half.The time has arrived for nationally coordinated action to substantiallyincrease intake of vitamin D and calcium. www.drbonci.com
  123. 123. “Because of the convincing evidence for benefit and the strongevidence of safety, we urge those who have the ability to supportpublic health—the media, vitamin manufacturers, and policy makers—to undertake new initiatives that will have a realistic chance ofmaking a difference in terms of vitamin D nutrition.” nutrition“We call for international agencies such as the Food and NutritionBoard and the European Commission’s Health and ConsumerProtection Directorate-General to reassess as a matter of highpriority their dietary recommendations for vitamin D, because theformal nationwide advice from health agencies needs to bechanged.” www.drbonci.com
  124. 124. Is Sun exposure Worth the Skin Cancer Risk?The U.S. economicburden due to vitamin Dinsufficiency frominadequate exposure tosolar UVB irradiance, diet,and supplements wasestimated at $40-56billion in 2004, whereasthe economic burden forexcess UV irradiance wasestimated at $6-7 billion. billionPhotochem Photobiol. 2005 Nov-Dec;81(6):1276-86. www.drbonci.com
  125. 125. Deficiency Death Toll We estimate that 50,000-63,000 individuals in the United States and 19,000- 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D. Photochem Photobiol. 2005 Nov-Dec;81(6):1276-86. www.drbonci.com
  126. 126. An Ethical Question?The recent discovery thatsupplemental cholecalciferol(vitamin D) significantly reduces all-cause mortality emphasizes themedical, ethical, and legalimplications of promptlydiagnosing and adequately treatingvitamin D deficiency. Altern Med Rev. 2008 Mar;13(1):6-20. www.drbonci.com
  127. 127. Prevalence of Low Vitamin D 40In this study of vitamin D n = 512 38.5status in 512 women: 37.5 30 ● 37.5% were deficient 38.5% were insufficient Percentage ● ● 24% were adequate 20 24Adequate is 30 ng/mL or 10 higher (73 nmol/L). 0 CA: A Cancer Journal for Clinicians. 2008 Deficient Insufficient Adequate Sep/Oct;58:264-265. Vitamin D Status www.drbonci.com
  128. 128. Vitamin D and Breast Cancer Survival• Women with breast 2.0 n = 512, cancer who had 12 yrs Cancer Free Survival (RR) 1.94 adequate serum vitamin 1.5 D levels (30+ ng/mL) ng/mL had nearly twice the survival rate after 12 1.0 1.00 years of follow-up than vitamin D deficient 0.5 (<20 ng/mL) women. ng/mL 0.0 CA: A Cancer Journal for Clinicians. 2008 Low Adequate Sep/Oct;58:264-265. Serum Vitamin D Status www.drbonci.com
  129. 129. Breast Cancer www.drbonci.com
  130. 130. Colorectal Cancer www.drbonci.com
  131. 131. Vitamin D and Cancer Preventionhttp://www.grassrootshealth.net/media/download/disease_incidence_prev_chart_101608.pdf www.drbonci.com
  132. 132. DINOMIT Theory of CancerDisjunctionInitiation (genetic variation)Natural selectionOvergrowthMetastasis (spread)Involution (cancer stops or slows)Transition (becomes chronic condition)Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  133. 133. Disjunction [D]isjunction, consist[s] of substantial weakening or loss of adherence between epithelial cells within a tissue compartment. Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  134. 134. DisjunctionExistence of thecapability of human cellsfor disjunction andrapid autonomousproliferation is notsurprising, since it isneeded for growth andhealing of injuries.Cell. 1996;84:345–357. www.drbonci.com
  135. 135. Disjunction DNA may facilitate the capability of the human cell for autonomous decoupling from a basement membrane, and the mobility that is needed for reproduction and functioning of the cellular immune system. Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  136. 136. InitiationThe critical events aremost likelyuncorrected errorsthat occur during DNAreplication or, at times,action on the DNA ofalkylating agents,ionizing radiation, orepigenetic factors.Br J Cancer. 2009;100:571–577. www.drbonci.com
  137. 137. Natural Selection This phase consists of selection of the fastest reproducing, most aggressive cells. It is a well described process of evolution, yet occurring on a microscopic scale. Land RB. Genetics and reproduction. In: Austin CR, Short RV, eds. Reproduction in mammals: reproductive fitness. Cambridge: Cambridge University Press; 1985:3 www.drbonci.com
  138. 138. Natural SelectionSince the driver of evolution isthe gene, a stem cell having agene associated with fasterreproduction or aggressionagainst other cells incompetition for limitedresources, will eventually beoverrepresented in the tissuecompartment.Dawkins R. The selfish gene. New York: Oxford University Press; 2006.Nutr Rev. 2007;65:S91–95. www.drbonci.com
  139. 139. Overgrowth The next phase is clonal expansion, or overgrowth of the tumor outside the basement membrane of the tissue and into the stromal layer; it occurs for unknown reasons. Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  140. 140. OvergrowthAggressive cells nearthe basementmembrane may begin todissolve itenzymatically or bychanging extracellularpH, in order to obtainneeded amino acids.Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  141. 141. Metastasis The next phase is metastasis, which may be regarded as analogous to colonization of a remote range by an organism. Invasion of distal tissues could be facilitated by disjunction in the remote tissue, reducing its barrier function. Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  142. 142. InvolutionThe next phase isinvolution, which occurswhen vitamin D status isrestored by a seasonal risein 25(OH)D; it consists of atemporary arrest ofgrowth of metastases andother progeny of theprimary tumor whose VDRis intact.Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  143. 143. Involution During the involution phase, malignant cells remain in the metastases, but intercellular junctions may be re- established in cells that have functional VDR. Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  144. 144. TransitionIf vitamin D and calciumdeficiency persist andthe metastatic lesionsdo not irretrievablyharm a vital organ, themetastatic cancer willmake a transition tocarcinomatosis, ordisseminatedmalignancy.Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  145. 145. Transition If vitamin D and calcium are repleted to adequate levels, some evidence suggests that there may be a transition from an acute to a chronic disease. Ann Epidemiol. 2009 Jul;19(7):468-83. www.drbonci.com
  146. 146. Transition[T]he VDR receptor-ligand complex activatessignaling pathways thatinduce E-cadherinand other proteins thatadhere cells to oneanother, including zonaoccludens proteins 1and 2.J Cell Biol. 2008;183:697–710.Anticancer Res. 2008;28:2613–2623. www.drbonci.com
  147. 147. D, Season and Survivability Patients diagnosed during the summer and autumn had the best prognosis (Ralative risk (RR) death 0.8; 95% CI 0.75-0.85). The seasonal effect on prognosis may be related to the seasonal variations of calcidiol (the marker of vitamin D status). J. Prostate. 2007 Sep 1;67(12):1362-70. www.drbonci.com
  148. 148. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 152
  149. 149. Time Cycles www.drbonci.com 153
  150. 150. The Tyranny of TimeWe have become a “clock driven” society, onethat arranges time according to the demands of acommercial or industrial complex often fosteredby profit and/or leisure, rather than arrangingtime so that our internal clocks are in synchronywith the natural environment of this “clockworkEarth.”Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 11 www.drbonci.com 154
  151. 151. Three rhythm domains ● Circadian (20 to 28 hours) ● Ultradian (< 20 hours) ● Infradian (> 28 hours)Koukkari and Sothern. Introduction to Biological Rhythms. 2006.p. 15 www.drbonci.com 155
  152. 152. Examples of biological rhythms ● Circadian: body temperature in humans and leaf movements of plants. ● Ultradian: brain waves of humans and twining of movements of bean shoots. ● Infradian: the menstrual cycle of human females and the annual germination of certain seeds.Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 15 www.drbonci.com 156
  153. 153. Circadian CycleOrganisms have to be able to extract time of day information from dawn and dusk. Foster & Kreitzman from Life Rhythms, 2005, p. 95. www.drbonci.com 157
  154. 154. Introduction to the CircadiaIn humans, like otherorganisms, mostphysiological and behavioralfunctions are manifestedrhythmically across daysand nights.When a human being encounters a new day, the bodyprepares itself for the new tasks ahead and boostheart rate, blood pressure and temperature.Journal of Circadian Rhythms 2010, 8:3 www.drbonci.com 158
  155. 155. Circadian Clock These rhythms are the outward manifestation of an internal timing system generated by a circadian clock that is synchronized by the day-night cycle. Nature 2002 , 418:935-941. www.drbonci.com 159
  156. 156. Circadian ClockThe circadian timingsystem proficientlycoordinates thephysiology of livingorganisms to matchenvironmental orimposed 24-hour cycles.Nat Rev Neurosci 2003 , 4:649-661. www.drbonci.com 160
  157. 157. Circadian Clock Circadian clocks are endogenous and self- sustained time-tracking systems that enable organisms to anticipate environmental changes, thereby adapting their behavior and physiology to the appropriate time of day. Trends Neurosci 2002 , 25:632-637. www.drbonci.com 161
  158. 158. Circadian ClockA wide range ofbiological processes areregulated by thecircadian clockincluding sleep-wakecycles, bodytemperature, energymetabolism, cell cycleand hormone secretion.Annu Rev Genomics Hum Genet 2004 , 5:407-441.Curr Top Dev Biol 2007 , 78:173-216. www.drbonci.com 162
  159. 159. Master Clock The mammalian clock system is hierarchical with a master clock that controls circadian rhythms and resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. Journal of Circadian Rhythms 2010, 8:3 www.drbonci.com 163
  160. 160. Master ClockThe SCN pacemakerconsists of multiple,autonomous single cellcircadian oscillators,which are synchronizedto generate acoordinated rhythmicoutput in intact animals.Neuron 1995 , 14:697-706.Cell 1997 , 91:855-860. www.drbonci.com 164
  161. 161. Master Clock In mammals, the circadian photoreception pathways are distinct from those of visual perception. N Engl J Med 1995 , 332:6-11. Science 1999 , 284:502-504. Science 1999 , 284:505-507. www.drbonci.com 165
  162. 162. Master ClockLight is perceived by asubset of melanopsin-expressing retinalganglion cells, andthe photic information isdirectly conveyed to theSCN clock through theretino-hypothalamictract.Nature Neurosci 2001 , 4:1165.Science 2002 , 295:1065-1070.Science 2002 , 298:2213-2216. www.drbonci.com 166
  163. 163. Retinal MelanopsinMutant mice lacking rods and cones (blind) can,nevertheless, be entrained by light dark cycles. Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 37 www.drbonci.com 167
  164. 164. SCN Environmental SynchronizerThe suprachiasmaticnuclei (SCN) of thehypothalamus arenecessary forcoordination of majoraspects of circadianrhythmicity in mammals.Brain Res Mol Brain Res. 2004 May 19;124(2):143-51. www.drbonci.com 168
  165. 165. Master ClockThis photic entrainment corrects the phase of the SCNoscillator every day to ensure synchronization ofcircadian with geophysical time.Journal of Circadian Rhythms 2010, 8:3 www.drbonci.com 169
  166. 166. The Master ClockTo coordinate time-appropriate metabolicresponses in peripheraltissues, the rhythm ofSCN (suprachiasmaticnuclei) neuronal activitymust be entrained bythe dailyenvironmental cycle.Ann Acad Med Singapore. 2008 Aug;37(8):662-8. Review. www.drbonci.com 170
  167. 167. Master Clock In general terms, the period of the clock is genetically determined, whereas its phase is heavily influenced by environmental zeitgebers (cues or stimuli) such as light. Journal of Circadian Rhythms 2010, 8:3 www.drbonci.com 171
  168. 168. ZeitgeberThe major zeitgeber(time-giver) is lightintensity. Ann Acad Med Singapore. 2008Aug;37(8):662-8. ReviewOther zeitgegers includefood, temperature,exercise, socialinteraction and odor.The zeitgeber uses the neuroendocrine systemto entrain slave oscillators. www.drbonci.com 172
  169. 169. Slave Oscillators A major finding in the field of circadian rhythms in recent years is that the SCN is not the only circadian clock in the organism. Indeed, most tissues including extra-SCN brain regions and peripheral organs bear circadian oscillators. J Biol Rhythms 2003 , 18:250-260. www.drbonci.com 173
  170. 170. Slave OscillatorsThe SCNsynchronizesperipheral clocksin organs so that acoherent rhythm isorchestrated at theorganismal level toensure temporallycoordinatedphysiology.J Biol Rhythms 2001 , 16:196-204.Cell Tissue Res 2002 , 309:109-118Eur J Neurosci 1999 , 11:1535-1544. www.drbonci.com 174
  171. 171. Molecular Mechanismof the Circadian Clock The molecular clockwork is composed of a network of transcriptional- translational feedback loops that drive rhythmic, ~24-hour expression patterns of core clock components. Science 2000 , 288:1013-1019. www.drbonci.com 175
  172. 172. The Endogenous ClockThe clock consists ofinteracting moleculeswhose levels repeatedlyfluctuate every 24 hours.A time point is specifiedby the concentrationsof these molecules inthe nucleus andcytoplasm.Ann Acad Med Singapore. 2008 Aug;37(8):662-8. Review. www.drbonci.com 176
  173. 173. Molecular Mechanism of the Circadian ClockCore clock componentsare genes whoseprotein products arenecessary for thegeneration andregulation of circadianrhythms withinindividual cellsthroughout theorganism.J Biol Rhythms 2004 , 19:339-347. www.drbonci.com 177
  174. 174. Circadian Clock and Cell Cycle The circadian clock controls the expression of cell cycle- related genes. Circadian Clock Genes Science 2003 , 302:255-259. www.drbonci.com 178
  175. 175. Circadian Clock, DNA Damage Response and Tumor SuppressionDNA damage leads toactivation of criticalcomponents of cellularstress responsepathways which in turnactivates tumorsuppressor protein p53and subsequentlycauses cell cycle arrestor apoptosis.Nat Rev Mol Cell Biol 2008 , 9:402-412. www.drbonci.com 179
  176. 176. Clock-Cancer Connection Exposure to light-at- night, including disturbance of the circadian rhythm, possibly mediated via the melatonin synthesis and clock genes, has been suggested as a contributing cause of breast cancer. Journal of Circadian Rhythms 2010, 8:3 www.drbonci.com 180
  177. 177. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 181
  178. 178. How do you keep 50 Trillion cellsHappy, Healthy and Under Control? Entrainment www.drbonci.com 182
  179. 179. Entrainment In chronobiology, entrainment of a circadian system is the alignment of its own period and phase to the period and phase of an external rhythm. http://en.wikipedia.org/wiki/Entrainment_(chronobiology) www.drbonci.com 183
  180. 180. EntrainmentA common example is theentrainment ofendogenous circadianrhythms (which, inmammals, are generatedby the suprachiasmaticnuclei of thehypothalamus) to thedaily light-dark cycle.http://en.wikipedia.org/wiki/Entrainment_(chronobiology) www.drbonci.com 184
  181. 181. Chronobiologic FunctionIn animals, circulatinglevels of the hormonemelatonin vary in adaily cycle, therebyallowing theentrainment of thecircadian rhythms ofseveral biologicalfunctions.Int. J. Clin. Pract. 2007; 61 (5): 835–45. www.drbonci.com 185
  182. 182. The Survival Advantage The synchrony achieved between an organism’s metabolism and its environment confers a survival advantage. Ann Acad Med Singapore. 2008 Aug;37(8):662-8. Review. www.drbonci.com 186
  183. 183. The Natural Day v 24/7Prior to the early 1900s, the selective advantageto humans to synchronize their activities withthe daily and yearly motion of our planet was veryevident.Night was partitioned for rest and sleep, whiledaylight with a span for activity andmovement.People had little else to do at night but sleep.Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 377 www.drbonci.com 187
  184. 184. Time SchedulesRegardless of whateverschedules societyimposes or we impose,we are born with atemporal system ofrhythms as part of ourgenetic structure.Koukkari and Sothern. Introduction to Biological Rhythms. 2006.p. 378 www.drbonci.com 188
  185. 185. Time schedules Depending upon the circumstances there may be harmony or discord between our internal rhythms and the external clocks of our society. Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 379 www.drbonci.com 189
  186. 186. Artificial RhythmsLife moves in synchronyto the beat of clocksand calendars, someoutside the body andsome within the verycells of all living things.Koukkari and Sothern. Introduction to Biological Rhythms. 2006.p. 1 www.drbonci.com 190
  187. 187. Watches, Clocks,Calendars and Schedules These independent devices may be either in or out of phase with the biological clocks and rhythms of our body, which over millions of years, have adapted to the motions of our planet with its environmental cues as to when an activity should best occur. Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 376 www.drbonci.com 191
  188. 188. Circannual Cycle“Light canbe used tocalculatethe time ofyear.”Foster & Kreitzman from Life Rhythms,2005, p. 84. www.drbonci.com 192
  189. 189. Cultura MataToday, the trends inurbanization and theutilization of electricalpower and rapidtransportation shieldmost of us fromwitnessing much of theseasonal biologicaldiversity found innature.Koukkari and Sothern. Introduction to Biological Rhythms. 2006.p. 107 www.drbonci.com 193
  190. 190. Addaptaion to Light Availability Native plants and animals have become adapted to the seasons of their environment by responding to the changes in the lengths of daylight and night in preparation for climactic changes that are to come. Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 109 www.drbonci.com 194
  191. 191. PhotoperiodismThese responses, whichare associated with theseasons of the year,involve a physiologicalprocess known asphotoperiodism.Koukkari and Sothern. Introduction to Biological Rhythms. 2006.p. 109 www.drbonci.com 195
  192. 192. Light as Environmental SignalVisible light exposure modulates pituitary and pinealgland changes. Melatonin, norepinephrine, and acetylcholine decrease with light activation, whereas cortisol, serotonin, GABA, and dopamine levels increase. Ann N Y Acad Sci. 2000;917:435-45. www.drbonci.com 196
  193. 193. [With light activiation]... cortisol, serotonin,GABA, and dopamine levelsincrease. Ann N Y Acad Sci. 2000;917:435-45. www.drbonci.com 197
  194. 194. Dopamine: Helping Males Copulate for at least 200 Million Years Brain dopamine systems are implicated in a variety of behavioral responses and clinical syndromes, including sex, drug addiction, feeding, satiety, sleep, wakefulness, arousal, attention, reward, decision- making, depression, anxiety, psychosis, and movement disorders. Behav Neurosci. 2010 Dec;124(6):877-80. www.drbonci.com 198
  195. 195. Dopamine: Modulator of Food Seeking.The dopamine projectionto the nucleus accumbenshas been implicated inbehaviors directed towardthe acquisition andconsumption of naturalrewards.J Neurosci. 2004 Feb 11;24(6):1265-71. www.drbonci.com 199
  196. 196. Dopamine and Reward Dopamine is closely associated with reward-seeking behaviors, such as consumption and addiction. Nature. 2009 Jun 11;459(7248):837-41. “Addiction depends on Speed of Reward.” www.drbonci.com 200
  197. 197. Reduced MotivationIn humans, drugs that reduce dopamine activity(neuroleptics, e.g. antipsychotics: clozapine,haldol) have been shown to reduce motivation,cause anhedonia (inability to experiencepleasure), and long-term use has been associatedwith the irreversible movement disorder, tardivedyskinesia.Pharmacopsychiatry. 2003 Nov;36 Suppl 3:S181-90. www.drbonci.com 201
  198. 198. Light Exposure Increases Cortisol[B]right light increasedcortisol levels andbody temperature andimproved alertnesssignificantly.Pak J Biol Sci. 2010 May 1;13(9):431-6. www.drbonci.com 202
  199. 199. Cortisol Hunger In binge eating disorder, there is an hyperactive HPA axis related to abdominal obesity that persists even after treatment, suggesting that cortisol might be a primary factor in the disorder. Ann N Y Acad Sci. 2004 Dec;1032:202-7. www.drbonci.com 203
  200. 200. Light, Hyperglycemia & ObesityDisrupted light-darkcycle induces obesitywith hyperglycemia ingenetically intactanimals.Neuro Endocrinol Lett. 2009;30(4):458-61. www.drbonci.com 204
  201. 201. Light & Insulin Resistance Circadian misalignment may lead to central and peripheral deleterious consequences, such as memory deficit and insulin resistance. Front Neuroendocrinol. 1993 Oct;14(4):303-47. www.drbonci.com 205
  202. 202. Sleep and Glucose MetabolismUnder normalconditions, glucosetolerance is modulatedby circadianrhythmicity and sleep,two central nervoussystem processes whichmay be influenced bymelatonin.Therapie. 1998 Sep-Oct;53(5):467-72. www.drbonci.com 206
  203. 203. Cancer & ObesityCancers linked to Among men, cancersobesity among women linked to obesitycomprise approximately comprise approximately51% of all new cancers. 14% of new cancers. http://www.obesity.org/information/cancer_obesity.asp www.drbonci.com 207
  204. 204. Sleep Loss & ObesityCross-sectional andlongitudinalepidemiological studieshave shown associationsbetween short sleepduration and obesity,diabetes andhypertension.Obes Rev. 2009 Nov;10 Suppl 2:37-45. www.drbonci.com 208
  205. 205. Sleep Loss & ObesityAccumulating evidencefrom both epidemiologicstudies and well-controlled laboratorystudies indicates thatchronic partial sleeploss may increase therisk of obesity andweight gain.Endocr Dev. 2010;17:11-21. www.drbonci.com 209
  206. 206. Neuroendocrine Dysfunction & SleepEpidemiologic studies in adults and children andlaboratory studies in young adults indicate thatsleep restriction results in metabolic andendocrine alterations, including decreasedglucose tolerance, decreased insulin sensitivity,increased evening concentrations of cortisol,increased levels of ghrelin, decreased levels ofleptin and increased hunger and appetite.Endocr Dev. 2010;17:11-21. www.drbonci.com 210
  207. 207. Insulin Resistance & Sleep InterruptionFragmentation of sleepacross all stages isassociated with adecrease in insulinsensitivity.Chest. 2010 Jan;137(1):95-101. www.drbonci.com 211
  208. 208. Insulin Resistance & Cancer [H]yperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity- breast cancer relationship. J Natl Cancer Inst. 2009 Jan 7;101(1):48-60. www.drbonci.com 212
  209. 209. Insulin Resistance & Sleep InterruptionIncreases insympatheticnervous systemand adrenocorticalactivity likelymediate the adversemetabolic effects ofpoor sleep quality.Chest. 2010 Jan;137(1):95-101. www.drbonci.com 213
  210. 210. Poor Sleep Hygiene Compared to a few decades ago, adults, as well as children, sleep less. Sleeping as little as possible is often seen as an admirable behavior in contemporary society. Endocr Dev. 2010;17:11-21. www.drbonci.com 214
  211. 211. Light pollutionThe prevalent trend in human society to useartificial light has reached ruinous levelsthroughout much of the world such that nocturnalsky brightness has increased many fold fromnatural conditions.Illuminating the night and thereby extendingthe daylong past sunset is an ever increasingdilemma.Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 408 www.drbonci.com 215
  212. 212. Light Pollution & Health Ill-timed artificial lighting and the lack of sunlight may cause circadian disruption that can lead to health problems. Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 408 www.drbonci.com 216
  213. 213. Effects on Clinical HealthLight thus has the abilityto act like a drug and,as such, has become apublic health issue inthe industrialized world .Koukkari and Sothern. Introduction to Biological Rhythms. 2006.p. 408 www.drbonci.com 217
  214. 214. Effects on Clinical Health Areas possibly affected by changes in melatonin production include endocrine functions associated with puberty, psychiatric illness, stress related disorders, immune responses, and carcinogenesis. Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 408 www.drbonci.com 218
  215. 215. “Breathe-in Experience, Breathe-out Poetry.” Muriel Rukeyser quotes (American Writer, 1913-1980) www.drbonci.com 219
  216. 216. Mammalian Hibernation: A Naturally Reversible Model for Insulin Resistance in Man? Fat deposition occurs on a circannual basis. It is entrained by the length of daylight, with peak fat deposition occurring as days shorten in the autumn. Diab Vasc Dis Res. 2008 Jun;5(2):76-81. www.drbonci.com 220
  217. 217. Mammalian Hibernation: A Naturally Reversible Model for Insulin Resistance in Man?The circannual cycle ofhibernation exhibitssimilarities and differencesbetween the obligatory,yet reversible, naturalobesity and accompanyinginsulin resistance of naturalhibernation, and thepandemic of human obesityand metabolic syndrome.Diab Vasc Dis Res. 2008 Jun;5(2):76-81. www.drbonci.com 221
  218. 218. Prehibernation Insulin Resistance The bats showed high circulating blood glucose levels and impaired glucose tolerance during the period of fat deposition suggesting insulin resistance condition which improves after winter when most of the fat has been utilized as a metabolic fuel. Comp Biochem Physiol A Mol Integr Physiol. 2010 Mar;155(3):392-400. www.drbonci.com 222
  219. 219. Sleep Normalizes PhysiologyThe high circulating melatoninlevels during the period ofmaximum body fat at thebeginning of winter prepare thebats for winter dormancy bymodulating the glucosehomeostasis through affectingblood glucose levels, muscleand liver glycogen stores,insulin receptor and glucosetransporter 4 (GLUT 4)expression.Comp Biochem Physiol A Mol Integr Physiol. 2010 Mar;155(3):392-400. www.drbonci.com 223
  220. 220. Insulin Resistancein Mammalian Hibernators Mammals that undergo winter hibernation prepare by dramatically increasing food intake and consequently, body fat stores during the summer and early autumn. FASEB Journal. 2007;21:964.2 www.drbonci.com 224
  221. 221. Insulin Resistance in Mammalian HibernatorsSeveral species nearly double their body mass in theform of fat.FASEB Journal. 2007;21:964.2 www.drbonci.com 225
  222. 222. Insulin Resistance in Mammalian Hibernators The consequence of this significant increase in fat mass has been shown to be hyperinsulinemia, peripheral insulin resistance, and elevated serum glucose levels in all species investigated thus far.Elevated serum glucose has an antifreezeeffect. ~TS Wiley, et. al. FASEB Journal. 2007;21:964.2 www.drbonci.com 226
  223. 223. Hibernation Disease/ Endless Summer The diseases that we know to correlate with obesity— high blood pressure, heart disease, diabetes, cancer, and depression—are all really the result of a vestigial hibernation instinct brought on by too much artificial light. Lights Out: Sleep, Sugar, and Survival (T. S. Wiley) Loc. 2041-47 www.drbonci.com 227
  224. 224. Hibernation Disease/ Endless SummerMammal studies concur thatonce you start the hibernationpreparation cycle,hyperlipidemia (highcholesterol), high bloodpressure, and insulinresistance (leading to obesity)are normal states thatresolve themselves with theextended sleep that follows innature.Lights Out: Sleep, Sugar, and Survival (T. S. Wiley) Loc. 2041-47 www.drbonci.com 228
  225. 225. Entrain Yourself1.Entrain yourself to the planetary cycles of light-dark and the seasonal shifts to experience better health.2.Live in the cyclical tide of cholecalciferol and melatonin. www.drbonci.com 229
  226. 226. A Special Thank You! The entire MSCA DII Membership Dr. Russell Matthias Dr. Ron Manfredi Dr. Doran Nicholson I am honored by your friendship. www.drbonci.com 230

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