Bibliography of The Resolution Zone

Bibliography of The Resolution Zone

References for The Resolution Zone

CHAPTER 1: WHAT IS THE ZONE?

Sears B. The Zone. Regan Books. New York, NY (1995)

CHAPTER 4: OVERVIEW OF THE ZONE PRO-RESOLUTION NUTRITION SYSTEM: A DEFINED DIETARY PATHWAY TO THE ZONE

Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, Suematsu M, Hirose N, and von Zglinicki T. “Inflammation, but not telomere length, predicts successful ageing at extreme old age.” EBioMedicine 2:1549–1558 (2015)

Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, and Small SA. “Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults.” Nat Neurosci 17:11798–1803 (2014)

Das SK, Gilhooly CH, Golden JK, Pittas AG, Fuss PJ, Cheatham RA, Tyler S, Tsay M, McCrory MA, Lichtenstein AH, Dallal GE, Dutta C, Bhapkar MV, Delany

REFERENCES

JP, Saltzman E, and Roberts SB. “Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: A 1-y randomized controlled trial.” Am J Clin Nutr 85:1023–1030 (2007)

Davinelli S, Bertoglio JC, Zarrelli A, Pina R, and Scapagnini G. “A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract on oxidative stress biomarkers.” J Am Coll Nutr 34: Suppl 1:28–33 (2015)

Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, and Weber PC, Schaeffer EJ, Wolff SM, and Dinarello CA. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” N Engl J Med 320:265–271 (1989)

Fontana L, Villareal DT, Das SK, Smith SR, Meydani SN, Pittas AG, Klein S, Bhapkar M, Rochon J, Ravussin E, and Holloszy JO. “Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: A randomized clinical trial.” Aging Cell 15: 22–27 (2016)

Georgiou T, Neokleous A, Nikolaou D, and Sears B. “Pilot study for treating dry age-related macular degeneration (AMD) with high-dose omega-3 fatty acids.” PharmaNutrition 2:8–11 (2014)

Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, Scott T, Redman LM, Stein R, Gilhooly CH, Stewart T, Robinson L, and Roberts SB. “Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: The CALERIE 2 randomized clinical trial.” JAMA Intern Med 176: 743–752 (2016)

McNamara RK, Perry M, and Sears, B. “Dissociation of C-reactive protein levels from long-chain omega-3 fatty acid status and anti-depressant response in adolescents with major depressive disorder: An open-label dose-ranging trial.” J Nutr Therapeutics 2:235–243 (2013)

Meydani M, Das S, Band M, Epstein S, and Roberts S. “The effect of caloric restriction and glycemic load on measures of oxidative stress and antioxidants in humans: Results from the CALERIE trial of human caloric restriction.” J Nutr Health Aging 15:456–60 (2011)

Pittas AG, Das SK, Hajduk CL, Golden J, Saltzman E, Stark PC, Greenberg AS, and Roberts SB. “A low-glycemic load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE trial.” Diabetes Care 28:2939–41 (2005)

Rabassa M, Cherubini A, Zamora-Ros R, Urpi-Sarda M, Bandinelli S, Ferrucci L, and Andres-Lacueva C. “Low levels of a urinary biomarker of dietary polyphenol are associated with substantial cognitive decline over a 3-year period in older adults: The Invecchiare in Chianti study.” J Am Geriatr Soc 63:938–946 (2015)

Rabassa M, Zamora-Ros R, Andres-Lacueva C, Urpi-Sarda M, Bandinelli S, Ferrucci L, and Cherubini A. “Association between both total baseline urinary and dietary polyphenols and substantial physical performance decline risk in older adults: A 9-year follow-up of the InCHIANTI study.” J Nutr Health Aging 20:478–485 (2016)

Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, and Roberts SB. “A 2-year randomized controlled trial of human caloric restriction: Feasibility and effects on predictors of healthspan and longevity.” J Gerontol A Biol Sci Med Sci. 70:1097–104 (2015)

Romashkan SV, Das SK, Villareal DT, Ravussin E, Redman LM, Rochon J, Bhapkar M, and Kraus WE. “Safety of two-year caloric restriction in non-obese healthy individuals.” Oncotarget 7: 19124–19133 (2016)

Sears, B. The Zone. Regan Books. New York, NY (1995)

Sears B, Bailes J, and Asselin B. “Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury.” PharmaNutrition 1: 86–89 (2013)

Sorgi PJ, Hallowell EM, Hutchins HL, and Sears B. “Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder Nutr J 13: 16 (2007)

Urpi-Sarda M, Andres-Lacueva C, Rabassa M, Ruggiero C, Zamora-Ros R, Bandinelli S, Ferrucci L, and Cherubini A. “The relationship between urinary total polyphenols and the frailty phenotype in a community-dwelling older population: The InCHIANTI study.” J Gerontol A Biol Sci Med Sci 70: 1141– 1147 (2015)

Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He Q, Curb JD, and Suzuki M. “Caloric restriction, the traditional Okinawan diet, and healthy aging: The diet of the world’s longest-lived people and its potential impact on morbidity and life span.” Ann N Y Acad Sci 1114:434–455 (2007

Willcox DC, Willcox BJ, Todoriki H, Curb JD, and Suzuki M. “Caloric restriction and human longevity: What can we learn from the Okinawans?” Biogerontology 7:173–177 (2006)

Zamora-Ros R, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, and Andres-Lacueva C. “High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults.” J Nutr 143:1445–1450 (2013)

CHAPTER 5: HOW INFLAMMATION KEEPS YOU ALIVE AND THE RESOLUTION RESPONSE KEEPS YOU WELL

Afonso PV, Janka-Junttila M, Lee YJ, McCann CP, Oliver CM, Aamer KA, Losert W, Cicerone MT, and Parent CA. “LTB4 is a signal-relay molecule during neutrophil chemotaxis.” Dev Cell 22: 1079–1091 (2012)

Baker RG, Hayden MS, and Ghosh S. “NF-κB, inflammation, and metabolic disease.” Cell Metab 13: 11–22 (2011)

Bierhaus A, Stern DM, and Nawroth PP. “RAGE in inflammation: A new therapeutic target?” Curr Opin Investig Drugs 7: 985–991 (2006)

Cai D. “Neuroinflammation and neurodegeneration in overnutrition-induced diseases.” Trends Endocrinol Metab 24: 40–47 (2013)

Camandola S, Leonarduzzi G, Musso T, Varesio L, Carini R, Scavazza A, Chiarpotto E, Baeuerle PA, and Poli G. “Nuclear factor-ϰB is activated by arachidonic acid but not by eicosapentaenoic acid.” Biochem Biophys Res Commun 229: 643–647 (1996)

Canetti C, Silva JS, Ferreira SH, and Cunha FQ. “Tumour necrosis factor-alpha and leukotriene B(4) mediate the neutrophil migration in immune inflammation.” Br J Pharmacol 134:1619–28 (2001)

Crofts CAP, Zinn C, Wheldon MC, and Schofield GM. “Hyperinsulinemia: A unifying theory of chronic disease?” Diabesity 1: 34–43 (2015)

Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, Williams AS, Lambie M, Foster TL, Liao CT, Rice CM, Greenhill CJ, Colmont CS, Hams E, Coles B, Kift-Morgan A, Newton Z, Craig KJ, Williams JD, Williams GT, Davies SJ, Humphreys IR, O’Donnell VB, Taylor PR, Jenkins BJ, Topley N, and Jones SA. “Interleukin-6 signaling drives fibrosis in unresolved inflammation.” Immunity 40: 40–50 (2014)

Gloire G, Legrand-Poels S, and Piette J. “NF-ϰB activation by reactive oxygen species: Fifteen years later.” Biochem Pharmacol 72: 1493–1505 (2006)

Guo H, Callaway JB, and Ting J. “Inflammasomes: Mechanism of action, role in disease and therapeutics.” Nat Med 21: 677–687 (2015)

Hardie DG. “Keeping the home fires burning: AMP-activated protein kinase.” J Royal Society Interface 15:20170774 (2018)

Hardie DG, Ross FA, and Hawley SA. “AMP-activated protein kinase: A target for drugs both ancient and modern.” Chem Bio 19: 1222–1236 (2012)

Huang S, Rutkowsky JM, Snodgrass RG, Ono-Moore KD, Schneider DA, Newman JW, Adams SH, and Hwang DH. “Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways.” J Lipid Res 53: 2002–2013 (2012)

Iwasaki A and Medzhitov R. “Control of adaptive immunity by the innate immune system.” Nat Immunol 16: 343–353 (2015)

Kawai T and Akira S. “The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors.” Nat Immunol 11: 373–384 (2010)

Sanchez-Galan E, Gomez-Hernandez A, Vidal C, Martin-Ventura JL, Blanco-Colio LM, Munoz-Garcia B, Ortega L, Egido J, and Tunón J. “Leukotriene B4 enhances the activity of nuclear factor-kappaB pathway through BLT1 and BLT2 receptors in atherosclerosis.” Cardiovasc Res 81: 216–225 (2009)

Sen R and Baltimore D. “Multiple nuclear factors interact with the immunoglobulin enhancer sequences.” Cell 46: 705–716 (1986)

Serhan CN, Ward PA, and Gilroy DW, and Samir S. Fundamentals of Inflammation. Cambridge University Press. Cambridge, UK (2010)

Serhan CN. “Pro-resolving lipid mediators are leads for resolution physiology.” Nature 510: 92–101 (2014)

Tobon-Velasco JC, Cuevas E, and Torres-Ramos MA. “Receptor for AGEs (RAGE) as mediator of NF-κB pathway activation in neuroinflammation and oxidative stress.” CNS Neurol Disord Drug Targets 13: 1615–1626 (2014)

Trowbridge HO and Emling RC. Inflammation: A Review of the Process. Quintessence Publising. Chicago, IL (1997)

Volchenkov R, Sprater F, Vogelsang P, and Appel S. “The 2011 Nobel Prize in physiology or medicine.” Scand J Immunol 75: 1–4 (2012)

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, and Ferrante AW. “Obesity is associated with macrophage accumulation in adipose tissue.” J Clin Invest 112: 1796–1808 (2003)

Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, Sgonc R, and Wolfram D. “The immunology of fibrosis.” Annu Rev Immunol 31: 107–135 (2013)

Yan SF, Ramasamy R, and Schmidt AM. “Mechanisms of disease: Advanced glycation end-products and their receptor in inflammation and diabetes complications.” Nat Clin Pract Endocrinol Metab 4: 285–293 (2008)

Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, and Cohen RA. “Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL- receptor-deficient mice.” Diabetes 55: 2180–2191 (2006)

Zhang Q, Lenardo MJ, and Baltimore D. “30 years of NF-κB: A blossoming of relevance to human pathobiology.” Cell 168: 37–57 (2017)

Zhang X, Zhang G, Zhang H, Karin M, Bai H, and Cai D. “Hypothalamic IKKbeta/ NF-κB and ER stress link overnutrition to energy imbalance and obesity.” Cell 135: 61–73 (2008)

CHAPTER 6: DIET-INDUCED INFLAMMATION

Brenner RR. “Nutritional and hormonal factors influencing desaturation of essential fatty acids.” Prog Lipid Res 20: 41–47 (1981)

De Fina LF. Vega GL. Leonard D. and Grundy SM. “Fasting glucose, obesity, and metabolic syndrome as predictors of type 2 diabetes: The Cooper Center longitudinal study.” J Investig Med 60: 1164–1168 (2012)

Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, and Ludwig DS. “Effects of dietary composition on energy expenditure during weight-loss maintenance.” JAMA 307: 2627–2634 (2012)

Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaeffer EJ, Wolff SM, and Dinarello CA. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” N Engl J Med 320: 265–271 (1989) 

Foster-Powell K, Holt SH, and Brand-Miller JC. “International table of glycemic index and glycemic load values: 2002.” Am J Clin Nutr 76: 5–56 (2002)

Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, and McConnell JP. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: Observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257–263 (2013)

Levitan EB, Liu S, Stampfer MJ, Cook NR, Rexrode KM, Ridker PM, Buring JE, and Manson JE. “HbA1c measured in stored erythrocytes and mortality rate among middle-aged and older women.” Diabetologia 51: 267–275 (2008)

Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, and Roberts SB. “High glycemic index foods, overeating, and obesity.” Pediatrics 103: E26 (1999)

McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D, Simon J, and Krauss RM. “Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease?” Am J Cardiol 96: 399–404 (2005)

Moss M. Salt Sugar Fat: How the Food Giants Hooked Us. Random House. New York (2014)

Ohnishi H and Saito Y. “Eicosapentaenoic acid (EPA) reduces cardiovascular events: Relationship with the EPA/arachidonic acid ratio.” J Atheroscler Thromb 20: 861–877 (2013)

Rahman I, Biswas SK, and Kirkham PA. “Regulation of inflammation and redox signaling by dietary polyphenols.” Biochem Pharmacol 72: 1439–52 (2006)

Salazar MR, Carbajal HA, Espeche WG, Leiva Sisnieguez CE, March CE, Balbin E, Dulbecco CA, Aizpurúa M, Marillet AG, and Reaven GM. “Comparison of the abilities of the plasma triglyceride/high-density lipoprotein cholesterol ratio and the metabolic syndrome to identify insulin resistance.” Diab Vasc Dis Res 10: 346–52 (2013)

Sánchez-Galán E, Gómez-Hernández A, Vidal C, Martín-Ventura JL, Blanco-Colio LM, Muñoz-García B, Ortega L, Egido J, and Tuñón J. “Leukotriene B4 enhances the activity of nuclear factor-kappaB pathway through BLT1 and BLT2 receptors in atherosclerosis.” Cardiovasc Res 81: 216–225 (2009)

Sears B. The Zone. Regan Books. New York, NY (1995) Sears B. OmegaRx Zone. Regan Books. New York, NY (2001)

Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005) Sears, B. Toxic Fat. Thomas Nelson. Knoxville, TN (2008)

Sears B. The Mediterranean Zone. Ballantine Books. New York, NY (2014)

Silver MJ, Hoch W, Kocsis JJ, Ingerman CM, and Smith JB. “Arachidonic acid causes sudden death in rabbits.” Science 183: 1085–1087 (1974)

Spite M, Claria J, and Serhan CN. “Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases.” Cell Metab 19: 21–36 (2014)

Wei D, Li J, Shen M, Jia W, Chen N, Chen T, Su D, Tian H, Zheng S, Dai Y, and Zhao A. “Cellular production of n-3 PUFAs and reduction of n-6-to-n-3 ratios in the pancreatic beta-cells and islets enhance insulin secretion and confer protection against cytokine-induced cell death.” Diabetes 59:471–478 (2010)

Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, and Clinton SK. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91: 1185–1194 (2010)

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis.” Lancet 369: 1090–1098 (2007)

Zhang X, Zhang G, Zhang H, Karin M, Bai H, and Cai D. “Hypothalamic IKKbeta/ NF-κB and ER stress link overnutrition to energy imbalance and obesity.” Cell 135:61–73 (2008)

CHAPTER 7: MARKERS OF THE ZONE

Adams PB, Lawson S, Sanigorski A, and Sinclair AJ. “Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression.” Lipids 31 (Suppl): S157–161 (1996)

Aggarwal V, Schneider AL, and Selvin E. “Low hemoglobin A(1c) in nondiabetic adults: An elevated risk state?” Diabetes Care 35: 2055–2060 (2012)

Carson AP, Fox CS, McGuire DK, Levitan EB, Laclaustra M, Mann DM, and Muntner P. “Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes.” Circ Cardiovasc Qual Outcomes. 3: 661–667 (2010)

Chilton FH, Patel M, Fonteh AN, Hubbard WC, and Triggiani M. “Dietary n-3 fatty acid effects on neutrophil lipid composition and mediator production. Influence of duration and dosage.” J Clin Invest. 91: 115–22 (1993)

Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaeffer EJ, Wolff SM, and Dinarello CA. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” N Engl J Med 320: 265–271 (1989)

Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35: 499–507 (2005)

Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, and Lodi L. “Cognitive and physiological effects of omega-3 polyunsaturated fatty acid supplementation in healthy subjects.” Eur J Clin Invest 35: 691–699 (2005)

Fukuda Y, Hashimoto Y, Hamaguchi M, Fukuda T, Nakamura N, Ohbora A, Kato T, Kojima T, and Fukui M. “Triglycerides to high-density lipoprotein cholesterol ratio is an independent predictor of incident fatty liver; a population-based cohort study.” Liver Int 36: 713–720 (2016)

Georgiou T and Prokopiou E. “The new era of omega-3 fatty acids supplementation: Therapeutic effects on dry age-related macular degeneration.” J Stem Cells 10: 205–215 (2015)

Harris WS. “The omega-3 index: Clinical utility for therapeutic intervention.” Curr Cardiol Rep 12: 503–508 (2010)

Harris WS, Luo J, Pottala JV, Espeland MA, Margolis KL, Manson JE, Wang L, Brasky TM, and Robinson JG. “Red blood cell polyunsaturated fatty acids and mortality in the Women’s Health Initiative Memory Study.” J Clin Lipidol 11: 250–259 (2017)

Hasegawa T, Otsuka K, Iguchi T, Matsumoto K, Ehara S, Nakata S, Nishimura S, Kataoka T, Shimada K, and Yoshiyama M. “Serum n-3 to n-6 polyunsaturated fatty acids ratio correlates with coronary plaque vulnerability: An optical coherence tomography study.” Heart Vessels 29: 596–602 (2014)

Holvoet P, Mertens A, Verhamme P, Bogaerts K, Beyens G, Verhaeghe R, Collen D, Muls E, and Van de Werf F. “Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease.” Arterioscler Thromb Vasc Biol 21: 844–848 (2001)

Holvoet P. “Oxidized LDL and coronary heart disease.” Acta Cardiol 59: 479–484 (2004)

Inoue K, Kishida K, Hirata A, Funahashi T, and Shimomura I. “Low serum eicosapentaenoic acid / arachidonic acid ratio in male subjects with visceral obesity.” Nutr Metab 10: 25 (2013)

Iwani NA, Jalaludin MY, Zin RM, Fuziah MZ, Hong JY, Abqariyah Y, Mokhtar AH, and Nazaimoon WM. “Triglyceride to HDL-C ratio is associated with insulin resistance in overweight and obese children.” Sci Rep 7: 40055 (2017)

Jiang Y, Djuric Z, Sen A, Ren J, Kuklev D, Waters I, Zhao L, Uhlson CL, Hong YH, Murphy RC, Normolle DP, Smith WL, and Brenner DE. “Biomarkers for personalizing omega-3 fatty acid dosing.” Cancer Prev Res 7: 1011–22 (2014)

Kawabata T, Hirota S, Hirayama T, Adachi N, Hagiwara C, Iwama N, Kamachi K, Araki E, Kawashima H, and Kiso Y. “Age-related changes of dietary intake and blood eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels in Japanese men and women.” Prostaglandins Leukot Essent Fatty Acids 84: 131–137 (2001)

Kitagawa M, Haji S, and Amagai T. “Elevated serum AA/EPA Ratio as a predictor of skeletal muscle depletion in cachexic patients with advanced gastro-intestinal cancers.” In Vivo 31: 1003–1009 (2017)

Kondo T, Ogawa K, Satake T, Kitazawa M, Taki K, Sugiyama S, and Ozawa T. “Plasma-free eicosapentaenoic acid/arachidonic acid ratio: A possible new coronary risk factor.” Clin Cardiol 9: 413–416 (1986)

McLaughlin T, Allison G, Abbasi F, Lamendola C, and Reaven G. “Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals.” Metabolism 53: 495–499 (2004) 

Nagai K, Koshiba H, Shibata S, Matsui T, and Kozaki K. “Correlation between the serum eicosapentaenoic acid-to-arachidonic acid ratio and the severity of cerebral white matter hyperintensities in older adults with memory disorder.” Geriatr Gerontol Int 15 (Suppl 1): 48–52 (2015)

Nagata M, Hata J, Hirakawa Y, Mukai N, Yoshida D, Ohara T, Kishimoto H, Kawano H, Kitazono T, Kiyohara Y, and Ninomiya T. “The ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cancer death in a Japanese community: The Hisayama Study.” J Epidemiol 27: 578–583 (2017)

Ninomiya T, Nagata M, Hata J, Hirakawa Y, Ozawa M, Yoshida D, Ohara T, Kishimoto H, Mukai N, Fukuhara M, Kitazono T, and Kiyohara Y. “Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: The Hisayama Study.” Atherosclerosis 231: 261–267 (2013)

Nishihira J, Tokashiki T, Higashiuesato Y, Willcox DC, Mattek N, Shinto L, Ohya Y, and Dodge HH. “Associations between serum omega-3 fatty acid levels and cognitive functions among community-dwelling octogenarians in Okinawa, Japan: The KOCOA study.” J Alzheimers Dis 51: 857–866 (2016)

Ohnishi H and Saito Y. “Eicosapentaenoic acid (EPA) reduces cardiovascular events: Relationship with the EPA/arachidonic acid ratio.” J Atheroscler Thromb 20: 861–877 (2013)

Rizzo AM, Montorfano G, Negroni M, Adorni L, Berselli P, Corsetto P, Wahle K, and Berra B. “A rapid method for determining arachidonic/eicosapentaenoic acid ratios in whole blood lipids: Correlation with erythrocyte membrane ratios and validation in a large Italian population of various ages and pathologies.” Lipids Health Dis 9: 7 (2010)

Rizzo AM, Corsetto PA, Montorfano G, Opizzi A, Faliva M, Giacosa A, Ricevuti G, Pelucchi C, Berra B, and Rondanelli M. “Comparison between the AA/ EPA ratio in depressed and non-depressed elderly females: Omega-3 fatty acid supplementation correlates with improved symptoms but does not change immunological parameters.” Nutr J 11: 82 (2012)

Salazar MR, Carbajal HA, Espeche WG, Leiva Sisnieguez CE, Balbín E, Dulbecco CA, Aizpurúa M, Marillet AG, and Reaven GM. “Relation among the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio, insulin resistance, and associated cardio-metabolic risk factors in men and women.” Am J Cardiol 109: 1749–1753 (2012)

Salazar MR, Carbajal HA, Espeche WG, Aizpurúa M, Dulbecco CA, and Reaven GM. “Comparison of two surrogate estimates of insulin resistance to predict cardiovascular disease in apparently healthy individuals.” Nutr Metab Cardiovasc Dis 27: 366–373 (2017)

Sears B. The OmegaRx Zone. Regan Books. New York, NY (2002)

Sears B. “Anti-inflammatory diets.” J Am Coll Nutr 34 (Suppl 1): 14–21 (2015)

Shibata M, Ohara T, Yoshida D, Hata J, Mukai N, Kawano H, Kanba S, Kitazono T, and Ninomiya T. “Association between the ratio of serum arachidonic acid to eicosapentaenoic acid and the presence of depressive symptoms in a general Japanese population: The Hisayama Study.” J Affect Disord 237: 73–79 (2018)

Sorgi PJ, Hallowell EM, Hutchins HL, and Sears B. “Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder.” Nutr J 6: 16 (2007)

Suwa M, Yamaguchi S, Komori T, Kajimoto S, and Kino M. “The association between cerebral white matter lesions and plasma omega-3 to omega-6 polyunsaturated fatty acids ratio to cognitive impairment development.” Biomed Res Int 2015: 153437 (2015) von Schacky C. “Omega-3 index and cardiovascular health.” Nutrients 6: 799–814 (2014)

Wakabayashi Y, Funayama H, Ugata Y, Taniguchi Y, Hoshino H, Ako J, and Momomura S. “Low eicosapentaenoic acid to arachidonic acid ratio is associated with thin-cap fibroatheroma determined by optical coherence tomography.” J Cardiol 66: 482–488 (2015)

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis.” Lancet 369: 1090–1098 (2007)

CHAPTER 8: ZONE DIET: REDUCING DIET-INDUCED INFLAMMATION

Agus MS, Swain JF, Larson CL, Eckert EA, and Ludwig DS. “Dietary composition and physiologic adaptations to energy restriction.” Am J Clin Nutr 71: 901–907 (2000)

Barlovic DP, Thomas MC, and Jandeleit-Dahm K. “Cardiovascular disease: What’s all the AGE/RAGE about?” Cardiovasc Hematol Disord Drug Targets. 10: 7–15 (2010)

Bierhaus A, Stern DM, and Nawroth PP. “RAGE in inflammation: A new therapeutic target?” Curr Opin Investig Drugs 7: 985–991 (2006)

Brattbakk HR, Arbo I, Aagaard S, Lindseth I, de Soysa AK, Langaas M, Kulseng B, Lindberg F, and Johansen B. “Balanced caloric macronutrient composition downregulates immunological gene expression in human blood cells-adipose tissue diverges.” OMICS 17: 41–52 (2013)

Brennan IM, Luscombe-Marsh ND, Seimon RV, Otto B, Horowitz M, Wishart JM, and Feinle-Bisset C. “Effects of fat, protein, and carbohydrate and protein load on appetite, plasma cholecystokinin, peptide YY, and ghrelin, and energy intake in lean and obese men.” Am J Physiol Gastrointest Liver Physiol 303: G129–140 (2012)

Brenner RR. Hormonal modulation of delta-6 and delta-5 desaturases: Case of diabetes.” Prostaglandins Leukot Essent Fatty Acids 68: 151–162 (2003) 

Bujak AL, Crane JD, Lally JS, Ford RJ, Kang SJ, Rebalka IA, Green AE, Kemp BE, Hawke TJ, Schertzer JD, and Steinberg GR. “AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging.” Cell Metab 21: 883–890 (2015)

Choquet H and Meyre D. “Genetics of obesity: What have we learned?” Curr Genomics 12: 169–179 (2011)

Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, and Ravussin E. “Calorie restriction increases muscle mitochondrial biogenesis in healthy humans.” PLoS Med 4: e76 (2007)

Das SK, Roberts SB, Bhapkar MV, Villareal DT, Fontana L, Martin CK, Racette SB, Fuss PJ, Kraus WE, Wong WW, Saltzman E, Pieper CF, Fielding RA, Schwartz AV, Ravussin E, and Redman LM. “Body-composition changes in the comprehensive assessment of long-term effects of reducing intake of energy (CALERIE)-2 study: A 2-y randomized controlled trial of calorie restriction in nonobese humans.” Am J Clin Nutr 105: 913–927 (2017)

Donaldson IJ and Göttgens B. “Evolution of candidate transcriptional regulatory motifs since the human-chimpanzee divergence.” Genome Biol 7: R52 (2006)

Dumesnil JG, Turgeon J, Tremblay A, Poirier P, Gilbert M, Gagnon L, St-Pierre S, Garneau C, Lemieux I, Pascot A, Bergeron J, and Despres JP. “Effect of a low- glycaemic index-low-fat-high protein diet on the atherogenic metabolic risk profile of abdominally obese men.” Br J Nutr 86: 557–568 (2001)

Eaton SB and Konner M. “Paleolithic nutrition. A consideration of its nature and current implications.” N Engl J Med 312: 283–289 (1985)

Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM, and Ludwig DS. “Effects of a low-glycemic load vs. low-fat diet in obese young adults: A randomized trial.” JAMA 297: 2092–2102 (2007)

Evangelista LS, Heber D, Li Z, Bowerman S, Hamilton MA, and Fonarow GC. “Reduced body weight and adiposity with a high-protein diet improves functional status, lipid profiles, glycemic control, and quality of life in patients with heart failure: A feasibility study.” J Cardiovasc Nurs 24: 207–215 (2009)

Fontana L, Villareal DT, Das SK, Smith SR, Meydani SN, Pittas AG, Klein S, Bhapkar M, Rochon J, Ravussin E, and Holloszy JO. “Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: A randomized clinical trial.” Aging Cell 15: 22–27 (2016)

Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35: 499–507 (2005)

Foster-Powell K, Holt SH, and Brand-Miller JC. “International table of glycemic index and glycemic load values: 2002.” Am J Clin Nutr 76: 5–56 (2002)

Gannon MC, Nuttall FQ, Saeed A, Jordan K, and Hoover H. “An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes.” Am J Clin Nutr 78: 734–741 (2003)

Gannon MC and Nuttall FQ. “Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition.” Nutr Metab 3: 16 (2006)

Hamdy O, Mottalib A, Morsi A, El-Sayed N, Goebel-Fabbri A, Arathuzik G, Shahar J, Kirpitch A, and Zrebiec J. “Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: A 5-year longitudinal study.” BMJ Open Diabetes Res Care 5:e000259 (2017)

Gilad Y, Oshlack A, Smyth GK, Speed TP, and White KP. “Expression profiling in primates reveals a rapid evolution of human transcription factors.” Nature 440: 242–245 (2006)

Hardie DG. “Keeping the home fires burning: AMP-activated protein kinase.” J Royal Society Interface 15: 20170774 (2018)

Hardie DG, Ross FA, and Hawley SA. “AMP-activate protein kinase: A target for drugs both ancient and modern.” Chem Bio 19: 1222–1236 (2012)

Institute of Medicine: Dietary Reference Intakes: Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC, National Academies Press. (2002)

Jenkins DJ, Wong JM, Kendall CW, Esfahani A, Ng VW, Leong TC, Faulkner DA, Vidgen E, Greaves KA, Paul G, and Singer W. “The effect of a plant-based low-carbohydrate diet on body weight and blood lipid concentrations in hyperlipidemic subjects.” Arch Intern Med 169: 1046–1054 (2009)

Johnston CS, Tjonn SL, and Swan PD. “High-protein, low-fat diets are effective for weight loss and favorably alter biomarkers in healthy adults.” J Nutr 134: 586–591 (2004)

Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, and Sears B. “Ketogenic low-carbohydrate diets have no metabolic advantage over non-ketogenic low- carbohydrate diets.” Am J Clin Nutr 83: 1055–1061 (2006)

Johnston CS, Tjonn SL, Swan PD, White A, and Sears B. “Low-carbohydrate, high-protein diets that restrict potassium-rich fruits and vegetables promote calciuria.” Osteoporos Int 17: 1820–1821 (2006)

Kajita K, Mune T, Ikeda T, Matsumoto M, Uno Y, Sugiyama C, Matsubara K, Morita H, Takemura M, Seishima M, Takeda J, and Ishizuka T. “Effect of fasting on PPARƴ and AMPK activity in adipocytes.” Diabetes Res Clin Pract 81:144–149 (2008)

Katsumata Y, Todoriki H, Higashiuesato Y, Yasura S, Willcox DC, Ohya Y, Willcox BJ, and Dodge HH. “Metabolic syndrome and cognitive decline among the oldest old in Okinawa: In search of a mechanism. The KOCOA project.” J Gerontol A Biol Sci Med Sci 67: 126–134 (2012) 

Katsumata Y, Todoriki H, Higashiuesato Y, Yasura S, Ohya Y, Willcox DC, and Dodge HH. “Very old adults with better memory function have higher low-density lipoprotein cholesterol levels and lower triglyceride to high-density lipoprotein cholesterol ratios: KOCOA project.” J Alzheimers Dis 34: 273–279 (2013)

Kernoff PB, Willis AL, Stone KJ, Davies JA, and McNicol GP. “Antithrombotic potential of dihomo-gamma-linolenic acid in man.” Br Med J 3: 1441–1444 (1977)

Kitabchi AE, McDaniel KA, Wan JY, Tylavsky FA, Jacovino CA, Sands CW, Nyenwe EA, and Stentz FB. “Effects of high-protein versus high-carbohydrate diets on markers of beta-cell function, oxidative stress, lipid peroxidation, proinflammatory cytokines, and adipokines in obese, premenopausal women without diabetes: A randomized controlled trial.” Diabetes Care 36:1 919–1925 (2013)

Kuipers RS, Luxwolda MF, Dijck-Brouwer DA, Eaton SB, Crawford MA, Cordain L, and Muskiet FA. “Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet.” Br J Nutr 104: 1666–1687 (2010)

Lasker DA, Evans EM, and Layman DK. “Moderate carbohydrate, moderate protein weight loss diet reduces cardiovascular disease risk compared to high carbohydrate, low protein diet in obese adults: A randomized clinical trial.” Nutr Metab 5: 30 (2008)

Layman DK, Shiue H, Sather C, Erickson DJ, and Baum J. “Increased dietary protein modifies glucose and insulin homeostasis in adult women during weight loss.” J Nutr 133: 405–410 (2003)

Layman DK, Boileau RA, Erickson DJ, Painter JE, Shiue H, Sather C, and Christou DD. “A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women.” J Nutr 133: 411–417 (2003)

Layman DK, Anthony TG, Rasmussen BB, Adams SH, Lynch CJ, Brinkworth GD, and Davis TA. “Defining meal requirements for protein to optimize metabolic roles of amino acids.” Am J Clin Nutr 101: 1330S–1338S (2015)

Layman DK, Evans EM, Erickson D, Seyler J, Weber J, Bagshaw D, Griel A, Psota T, and Kris-Etherton P. “A moderate-protein diet produces sustained weight loss and long-term changes in body composition and blood lipids in obese adults.” J Nutr 139: 514–521 (2009)

Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, and Roberts SB. “High glycemic index foods, overeating, and obesity.” Pediatrics 103: E26 (1999)

Ludwig DS. “The glycemic index: Physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.” JAMA 287: 2414–2423 (2002)

Liu K, Wang B, Zhou R, Lang HD, Ran L, Wang J, Li L, Kang C, Zhu XH, Zhang QY, Zhu JD, Doucette S, Kang JX, and Mi MT. “Effect of combined use of a low-carbohydrate, high-protein diet with omega-3 polyunsaturated fatty acid supplementation on glycemic control in newly diagnosed type 2 diabetes: A randomized, double-blind, parallel-controlled trial.” Am J Clin Nutr 108:256– 265 (2018) 

Mamerow MM, Mettler JA, English KL, Casperson SL, Arentson-Lantz E, Sheffield- Moore M, Layman DK, and Paddon-Jones D. “Dietary protein distribution positively influences 24-h muscle protein synthesis in healthy adults.” J Nutr 144: 876–80 (2014)

Markova M, Pivovarova O, Hornemann S, Sucher S, Frahnow T, Wegner K, Machann J, Petzke KJ, Hierholzer J, Lichtinghagen R, Herder C, Carstensen- Kirberg M, Roden M, Rudovich N, Klaus S, Thomann R, Schneeweiss R, Rohn S, and Pfeiffer AF. “Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes.” Gastroenterology 152: 571–585 (2017)

Markovic TP, Jenkins AB, Campbell LV, Furler SM, Kraegen EW, and Chisholm DJ. “The determinants of glycemic responses to diet restriction and weight loss in obesity and NIDDM.” Diabetes Care 21:687–694 (1998)

Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, and Anderson RM. “Caloric restriction improves health and survival of rhesus monkeys.” Nat Comm 8: 14063 (2017)

McCay CM, Crowell MF, and Maynard LA. “The effect of retarded growth upon the length of life span and upon the ultimate body size.” J Nutr 10: 63–79 (1935)

McDonald RB and Ramsey JJ. “Honoring Clive McCay and 75 years of calorie restriction research.” J Nutr 140: 1205–1210 (2010)

McLaughlin T, Allison G, Abbasi F, Lamendola C, and Reaven G. “Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals.” Metabolism 53: 495–499 (2004)

Mergenthaler P, Lindauer U, Dienel GA, and Meisel A. “Sugar for the brain: The role of glucose in physiological and pathological brain function.” Trends Neurosci 36: 587–597 (2013)

Moosheer SM, Waldschütz W, Itariu BK, Brath H, and Stulnig TM. “A protein- enriched low glycemic index diet with omega-3 polyunsaturated fatty acid supplementation exerts beneficial effects on metabolic control in type 2 diabetes.” Prim Care Diabetes. 8: 308–314 (2014)

Mottalib A, Sakr M, Shehabeldin M, and Hamdy O. “Diabetes remission after nonsurgical intensive lifestyle intervention in obese patients with type 2 diabetes.” J Diabetes Res 2015: 468704 (2015)

Nowick K, Gernat T, Almaas E, and Stubbs L. “Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain.” Proc Natl Acad Sci U S A. 106: 22358–22363 (2009)

Oates JA. “The 1982 Nobel Prize in Physiology or Medicine.” Science 218: 765–768 (1982)

Oeckinghaus A, Hayden MS, and Ghosh S. “Crosstalk in NF-κB signaling pathways.” Nat Immunol 12: 695–708 (2011) 

Owen OE, Felig P, Morgan AP, Wahren J, and Cahill GF. “Liver and kidney metabolism during prolonged starvation.” J Clin Invest 48: 574–583 (1969)

Parker B, Noakes M, Luscombe N and Clifton P. “Effect of a high-protein, high– monounsaturated fat weight loss diet on glycemic control and lipid levels in type 2 diabetes.” Diabetes Care 25: 425–430 (2002)

Pearce KL, Clifton PM, and Noakes M. “Egg consumption as part of an energy- restricted high-protein diet improves blood lipid and blood glucose profiles in individuals with type 2 diabetes.” Br J Nutr 105: 584–592 (2011)

Pereira MA, Swain J, Goldfine AB, Rifai N, and Ludwig DS. “Effects of a low- glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss.” JAMA 292: 2482–2490 (2004)

Pittas AG, Das SK, Hajduk CL, Golden J, Saltzman E, Stark PC, Greenberg AS, and Roberts SB. “A low-glycemic load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE trial.” Diabetes Care 28: 2939–2941 (2005)

Pittas AG, Roberts SB, Das SK, Gilhooly CH, Saltzman E, Golden J, Stark PC, and Greenberg AS. “The effects of the dietary glycemic load on type 2 diabetes risk factors during weight loss.” Obesity 14: 2200–2209 (2006)

Racette SB, Rochon J, Uhrich ML, Villareal DT, DAS SK, Fontana L, Bhapkar M, Martin CK, Redman LM, Fuss PJ, Roberts SB, and Kraus WE. “Effects of two years of calorie restriction on aerobic capacity and muscle strength.” Med Sci Sports Exerc 49: 2240–2249 (2017)

Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, and Roberts SB. “A 2-year randomized controlled trial of human caloric restriction: Feasibility and effects on predictors of healthspan and longevity.” J Gerontol A Biol Sci Med Sci 70: 1097–1104 (2015)

Roth JA, Etzioni R, Waters TM, Pettinger M, Rossouw JE, Anderson GL, Chlebowski RT, Manson JE, Hlatky M, Johnson KC, and Ramsey SD. “Economic return from the Women’s Health Initiative estrogen plus progestin clinical trial: A modeling study.” Ann Intern Med 160: 594–602 (2014)

Samuel VT and Shulman GI. “Mechanisms for insulin resistance: Common threads and missing links.” Cell 148: 852–871 (2012)

Sánchez-Galán E, Gómez-Hernández A, Vidal C, Martín-Ventura JL, Blanco-Colio LM, Muñoz-García B, Ortega L, Egido J, and Tuñón J. “Leukotriene B4 enhances the activity of nuclear factor-kappaB pathway through BLT1 and BLT2 receptors in atherosclerosis.” Cardiovasc Res 81: 216–225 (2009)

Sayegh AI. “The role of cholecystokinin receptors in the short-term control of food intake.” Prog Mol Biol Transl Sci 114: 277–316 (2013)

Sears B. The Zone. Regan Books. New York, NY (1995) 

Sears B. Mastering the Zone. Regan Books. New York, NY (1997) Sears B. The Anti-Aging Zone. Regan Books. New York, NY (1999) Sears B. The OmegaRx Zone. Regan Books. New York, NY (2002)

Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005) Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)

Sears B. The Mediterranean Zone. Ballantine Books. New York, NY (2014)

Sears B. “Phosphatidyl quarternary ammonium compounds.” U.S. Patent No. 4,086,257 (1978)

Sears B and Yesair DW. “Xenobiotic delivery vehicles.” U.S. Patent No. 4,298,594 (1981)

Sears B. “Synthetic phospholipid compounds.” U.S. Patent No. 4,426,330 (1984) Sears B and Perry M. “The role of fatty acids in insulin resistance.” Lipids Health Disease 14: 121 (2015)

Stentz FB, Brewer A, Wan J, Garber C, Daniels B, Sands C, and Kitabchi AE. “Remission of pre-diabetes to normal glucose tolerance in obese adults with high protein versus high carbohydrate diet.” BMJ Open Diabetes Res Care 4: e000258 (2016)

Stone KJ, Willis AL, Hart WM, Kirtland SJ, Kernoff PB, and McNicol GP. “The metabolism of dihomo-gamma-linolenic acid in man.” Lipids 14: 174–180 (1979)

Stulnig TM. “The Zone Diet and metabolic control in type 2 diabetes.” J Am Coll Nutr 34 Suppl 1: 39–41 (2015)

van der Klaauw AA, Keogh JM, Henning E, Trowse VM, Dhillo WS, Ghatei MA, and Farooqi IS. “High protein intake stimulates postprandial GLP-1 and PYY release.” Obesity 21:1602–1607 (2013)

White AM, Johnston CS, Swan PD, Tjonn SL, and Sears B. “Blood ketones are directly related to fatigue and perceived effort during exercise in overweight adults adhering to low-carbohydrate diets for weight loss: A Pilot study.” J Am Diet Assoc 107: 1792–1796 (2007)

Whitten P. “Stanford’s secret weapon.” Swimming World 34: 1–6 (1993)

CHAPTER 9: FERMENTABLE FIBER: THE KEY TO MAINTAINING GUT HEALTH

Anderson SC. The Psychobitoic Revolution. National Geographic Books. Washington DC (2017)

Anhê FF, Roy D, Pilon G, Dudonné S, Matamoros S, Varin TV, Garofalo C, Moine Q, Desjardins Y, Levy E, and Marette A. “A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in gut microbiota of mice.” Gut 64: 872–883 (2015)

Asarian L and Bächler T. “Neuroendocrine control of satiation.” Horm Mol Biol Clin Investig 19: 163–192 (2014)

Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, Sjostrom SL, Szewczykowska M, Jackowska T, Dos Remedios C, Malm T, Andrä M, Jashari R, Nyengaard JR, Possnert G, Jovinge S, Druid H, and Frisén J. “Dynamics of cell generation and turnover in the human heart.” Cell 161: 1566–1575 (2015)

Blasser MJ. Missing Microbes. Henry Holt. New York, NY (2014)

Bliss ES and Whiteside E. “The gut-brain axis, the human gut microbiota and their integration in the development of obesity.” Front Physiol 9: 900 (2018)

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, and Burcelin R. “Metabolic endotoxemia initiates obesity and insulin resistance.” Diabetes 56: 1761–1772 (2007)

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, and Bastelica D. “Metabolic endotoxemia initiates obesity and insulin resistance.” Diabetes 56: 1761–1772 (2007)

Caesasr R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, and Backhed F. “Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling.” Cell Metabol 22: 1–11 (2015)

Chambers ES, Morrison DJ, and Frost G. “Control of appetite and energy intake by SCFA: What are the potential underlying mechanisms?” Proc Nutr Soc 74: 328–336 (2015)

Chio CC, Baba T, and Black KL. “Selective blood-tumor barrier disruption by leukotrienes.” J Neurosurg 77: 407–410 (1992)

Christiansen CB, Gabe MBN, Svendsen B, Dragsted LO, Rosenkilde MM, and Holst JJ. “The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon.” Am J Physiol Gastrointest Liver Physiol 315: G53– G65 (2018)

Chronaiou A, Tsoli M, Kehagias I, Leotsinidis M, Kalfarentzos F, and Alexandrides TK. “Lower ghrelin levels and exaggerated postprandial peptide-YY, glucagon- like peptide-1, and insulin responses, after gastric fundus resection, in patients undergoing Roux-en-Y gastric bypass: A randomized clinical trial.” Obes Surg 22: 1761–1770 (2012)

Collen A. 10% Human. Harper Collins. New York, NY (2015)

Cornick S, Tawiah A, and Chadee K. “Roles and regulation of the mucus barrier in the gut.” Tissue Barriers 3: e982426 (2015)

Delcour JA, Aman P, Courtin CM, Hamaker BR, and Verbeke K. “Prebiotics, fermentable dietary fiber, and health claims.” Adv Nutr 7: 1–4 (2016)

Derrien M. “Akkermansia muciniphila, a human intestinal mucin-degrading bacterium.” Int J Systematic and Evolutionary Microbiology 54: 1469–1476 (2004)

Daud NM, Ismail NA, Thomas EL, Fitzpatrick JA, Bell JD, Swann JR, Costabile A, Childs CE, Pedersen C, Goldstone AP, and Frost GS. “The impact of oligofructose on stimulation of gut hormones, appetite regulation and adiposity.” Obesity 22: 1430–1438 (2014)

de Vogel-van den Bosch HM, Bünger M, de Groot PJ, Bosch-Vermeulen H, Hooiveld GJ, and Müller M. “PPARƴ-mediated effects of dietary lipids on intestinal barrier gene expression.” BMC Genomics 9: 231 (2008)

Everard A and Cani PD. “Gut microbiota and GLP-1.” Rev Endocr Metab Disord 15: 189–196 (2014)

Fasano A. “Zonulin and its regulation of intestinal barrier function: The biological door to inflammation, autoimmunity, and cancer.” Physiol Rev 91: 151–175 (2011)

Fredricks D. The Human Microbiota: How Microbial Communities Affect Health and Disease. Wiley-Blackwell. New York, NY (2013)

Gershon MD. The Second Brain. Harper Collins. New York, NY (1999)

Goodman BE. “Insights into digestion and absorption of major nutrients in humans.” Adv Physiol Educ 34: 44–53 (2010)

Greiner TU and Bäckhed F. “Microbial regulation of GLP-1 and L-cell biology.” Mol Metab 5: 753–758 (2016)

Grossi E and Pace F eds. Human Nutrition from the Gastroenterologist’s Perspective. Springer. New York, NY (2016)

Kaliannan K, Wang B, Xiang-Yong L, Kim K-J, and Kang JX. “A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia.” Sci Reports 5: 112276 (2015)

Kimura R, Takahashi N, Lin S, Goto T, Murota K, Nakata R, Inoue H, and Kawada “DHA attenuates postprandial hyperlipidemia via activating PPARƴ in intestinal epithelial cells.” J Lipid Res 54: 3258–3268 (2013)

Konturek SJ and Brzozowski T. “Role of leukotrienes and platelet activating factor in gastric mucosal damage and repair.” J Physiol Pharmacol 42:107–133 (1991)

Larraufie P, Martin-Gallausiaux C, Lapaque N, Dore J, Gribble FM, Reimann F, and Blottiere HM. “SCFAs strongly stimulate PYY production in human enteroendocrine cells.” Sci Rep 8: 74 (2018)

Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Stärkel P, Windey K, Tremaroli V, Bäckhed F, Verbeke K, de Timary P, and Delzenne NM. “Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol- dependence severity.” Proc Natl Acad Sci U S A 111: E4485–4493 (2014)

López-Moreno J, García-Carpintero S, Jimenez-Lucena R, Haro C, Rangel-Zúñiga OA, Blanco-Rojo R, Yubero-Serrano EM, Tinahones FJ, Delgado-Lista J, Pérez- Martínez P, Roche HM, López-Miranda J, and Camargo A. “Effect of dietary lipids on endotoxemia influences postprandial inflammatory response.” J Agric Food Chem 65: 7756–7763 (2017)

Lyte M and Cryan JF. Microbial Endocrinology: The Microbiota-Gut-Brain Axis. Springer. New York, NY (2014)

Masumoto S, Terao A, Yamamoto Y, Mukai T, Miura T, and Shoji T. “Non- absorbable apple procyandian prevent obesity associated with gut microbial and metabolomics changes.” Sci Reports 6: 31208 (2016)

Mayer E. The Mind-Gut Connection. Harper Wave. New York, NY (2016)

Nettleton JE, Reimer RA, and Shearer J. “Reshaping the gut microbiota: Impact of low-calorie sweeteners and the link to insulin resistance?” Physiol Behav164 (Pt B): 488–493 (2016)

Pelaseyed T, Bergström JH, Gustafsson JK, Ermund A, Birchenough GM, Schütte A, van der Post S, Svensson F, Rodríguez-Piñeiro AM, Nyström EE, Wising C, Johansson ME, and Hansson GC. “The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system.” Immunol Rev 260: 8–20 (2014)

Pepino MY, Tiemann CD, Patterson BW, Wice BM, and Klein S. “Sucralose affects glycemic and hormonal responses to an oral glucose load.” Diabetes Care 36: 2530–2535 (2013)

Pepino MY. “Metabolic effects of non-nutritive sweeteners.” Physiol Behav 152 (Pt B): 450–5 (2016)

Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR, and Frost G. “The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents.” Int J Obes 39: 424–429 (2015)

Roach M. Gulp. W.W. Norton and Company. New York, NY (2013)

Roopchand DE, Carmody RN, Kuhn P, Moskal K, Rojas-Silva, Turnbaugh PJ, and Raskin I. “Dietary polyphenols promote growth of gut bacterium Akkermansia muninphila and attenuate high-fat diet-induced metabolic syndrome.” Diabetes 64: 2847–2858 (2015)

Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, Gomis R, Claret M, and Cani PD. “Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders in mice.” Sci Reports 5: 16643 (2015)

Schroeder N, Marquart LF, and Gallaher DD. “The role of viscosity and fermentability of dietary fibers on satiety- and adiposity-related hormones in rats.” Nutrients 5: 2093–2113 (2013)

Slavin J. “Fiber and prebiotics.” Nutrients 5: 1417-1435 (2013)

Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, and Sonnenburg JL. “Diet-induced extinctions in the gut microbiota compound over generations.” Nature 529: 212–215 (2016)

Sonneburg J and Sonnenburg E. The Good Gut. Penguin Books. New York, NY (2016)

Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, and Frisén J. “Retrospective birth dating of cells in humans.” Cell 122: 133–143 (2005)

Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T, Concha H, Hassan M, Rydén M, Frisén J, and Arner P. “Dynamics of fat cell turnover in humans.” Nature 453: 783–787 (2008)

Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, and Frisén J. “Dynamics of hippocampal neurogenesis in adult humans.” Cell 153: 1219–1227 (2013)

Spreckley E and Murphy KG. “The L-cell in nutritional sensing and the regulation of appetite.” Front Nutr 2: 23 (2015)

Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, and Elinav E. “Artificial sweeteners induce glucose intolerance by altering the gut microbiota.” Nature 514: 181–186 (2014)

Tuohy K and Del Rio D. Diet-Microbe Interactions in the Gut. Academic Press. London, UK (2015)

van der Klaauw AA, Keogh JM, Henning E, Trowse VM, Dhillo WS, Ghatei MA, and Farooqi IS. “High protein intake stimulates postprandial GLP-1 and PYY release.” Obesity 21: 1602–1607 (2013)

Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, Salim Rasoel S, Tκth J, Holvoet L, Farré R, Van Oudenhove L, Boeckxstaens G, Verbeke K, and Tack J. “Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism.” Gut 63: 1293–1299 (2014)

Wrangham R. Cooking with Fire. Basic Books. New York, NY (2010)

Yeomans MR, Tepper BJ, Rietzschel J, and Prescott J. “Human hedonic responses to sweetness: Role of taste genetics and anatomy.” Physiol Behav 91: 264–273 (2007)

Zanchi D, Depoorter A, Egloff L, Haller S, Mählmann L, Lang UE, Drewe J, Beglinger C, Schmidt A, and Borgwardt S. “The impact of gut hormones on the neural circuit of appetite and satiety: A systematic review.” Neurosci Biobehav Rev 80: 457–475 (2017)

CHAPTER 10: OMEGA-3 FATTY ACIDS: AGENTS OF RESOLUTION

Arsenescu V, Arsenescu RI, King V, Swanson H, and Cassis LA. “Polychlorinated biphenyl-77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis.” Environ Health Perspect 116: 761– 768 (2008)

Ashley JT, Ward JS, Schafer MW, Stapleton HM, and Velinsky DJ. “Evaluating daily exposure to polychlorinated biphenyls and polybrominated diphenyl ethers in fish oil supplements.” Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 8: S1944–1957 (2010)

Bellenger J, Bellenger S, Bataille A, Massey KA, Nicolaou A, Rialland M, Tessier C, Kang JX, and Narce M. “High pancreatic n-3 fatty acids prevent STZ-induced diabetes in fat-1 mice: Inflammatory pathway inhibition. Diabetes 60: 1090– 1099 (2011)

Bhatt DL, Steg G, Mill M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Juliano RA, Jiao L, Granowitz G, Tardif JC, and Ballantyne CM. “Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.” N Engl J Med 380: 11–22 (2019)

Bhattacharya A, Chandrasekar B, Rahman MM, Banu J, Kang JX, and Fernandes “Inhibition of inflammatory response in transgenic fat-1 mice on a calorie- restricted diet.” Biochem Biophys Res Commun 349: 925–930 (2006)

Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, and Rawlings RR. “Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century.” Am J Clin Nutr 93: 950–962 (2011)

Bonds DE, Harrington M, Worrall BB, Bertoni AG, Eaton CB, Hsia J, Robinson J, Clemons TE, Fine LJ, and Chew EY. “Effect of long-chain n-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: Results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial.” JAMA Intern Med 174: 763–771 (2014)

Brenner RR. “Nutritional and hormonal factors influencing desaturation of essential fatty acids.” Prog Lipid Res 20: 41–7 (1981)

Brenner RR. Hormonal modulation of delta 6 and delta 5 desaturases: Case of diabetes.” Prostaglandins Leukot Essent Fatty Acids 68: 151–162 (2003)

Calder PC. “Omega-3 fatty acids and inflammatory processes: From molecules to man.” Biochem Soc Trans 45: 1105–1115 (2017)

Chen CT and Bazinet RP. “β-oxidation and rapid metabolism, but not uptake regulate brain eicosapentaenoic acid levels.” Prostaglandins Leukot Essent Fatty Acids 92: 33–40 (2015)

Elajami TK, Colas RA, Dalli J, Chiang N, Serhan CN, and Welty FK. “Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling.” FASEB J 30: 2792-2801 (2016)

el Boustani S, Causse JE, Descomps B, Monnier L, Mendy F, and Crastes de Paulet “Direct in vivo characterization of delta 5 desaturase activity in humans by deuterium labeling: Effect of insulin.” Metabolism 38: 315–321 (1989)

Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaeffer EJ, Wolff SM, and Dinarello CA. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” N Engl J Med 320: 265–271 (1989)

Georgiou T, Neokleous A, Nikolaou D, and Sears B. “Pilot study for treating dry age-related macular degeneration (AMD) with high-dose omega-3 fatty acids.” PharmaNutrition 2:8–11 (2014)

Georgiou T and Prokopiou E. “The new era of omega-3 fatty acids supplementation: Therapeutic effects on dry age-related macular degeneration.” J Stem Cells 10: 205–215 (2015)

Germano M, Meleleo D, Montorfano G, Adorni L, Negroni M, Berra B, and Rizzo AM. “Plasma, red blood cells, phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD).” Nutr Neurosci 10: 1–9 (2007)

Griffitts J, Saunders D, Tesiram YA, Reid GE, Salih A, Liu S, Lydic TA, Busik JV, Kang JX, and Towner RA. “Non-mammalian fat-1 gene prevents neoplasia when introduced to a mouse hepatocarcinogenesis model: Omega-3 fatty acids prevent liver neoplasia.” Biochim Biophys Acta 1801: 1133–1144 (2010)

Hansen JB, Olsen JO, Wilsgard L, Lyngmo V, and Svensson B. “Comparative effects of prolonged intake of highly purified fish oils as ethyl ester or triglyceride on lipids, haemostasis and platelet function in normolipaemic men.” Eur J Clin Nutr 47: 497–507 (1993)

Harris WS. “The omega-3 index: Clinical utility for therapeutic intervention.” Curr Cardiol Rep 12: 503–508 (2010)

Harris WS, Luo J, Pottala JV, Espeland MA, Margolis KL, Manson JE, Wang L, Brasky TM, and Robinson JG. “Red blood cell polyunsaturated fatty acids and mortality in the Women’s Health Initiative Memory study.” J Clin Lipidol 11: 250–259 (2017)

Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, and McConnell JP. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: Observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88: 257–263 (2013)

Heydari B, Abdullah S, Pottala JV, Shah R, Abbasi S, Mandry D, Francis SA, Lumish H, Ghoshhajra BB, Hoffmann U, Appelbaum E, Feng JH, Blankstein R, Steigner M, McConnell JP, Harris W, Antman EM, Jerosch-Herold M, and Kwong RY. “Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction: The OMEGA-REMODEL randomized clinical trial.” Circulation 134: 378–391 (2016)

Igarashi M, Chang L, Ma K, and Rapoport SI. “Kinetics of eicosapentaenoic acid in brain, heart and liver of conscious rats fed a high n-3 PUFA containing diet.” Prostaglandins Leukot Essent Fatty Acids 89: 403–412 (2013)

Innes JK and Calder PC. “Omega-6 fatty acids and inflammation.” Prostaglandins Leukot Essent Fatty Acids 132: 41–48 (2018)

Kang JX, Wang J, Wu L, and Kang ZB. “Transgenic mice: Fat-1 mice convert n-6 to n-3 fatty acids.” Nature 427: 504 (2004)

Kawabata T, Hirota S, Hirayama T, Adachi N, Kaneko Y, Iwama N, Kamachi K, Araki E, Kawashima H, and Kiso Y. “Associations between dietary n-6 and n-3 fatty acids and arachidonic acid compositions in plasma and erythrocytes in young and elderly Japanese volunteers.” Lipids Health Dis 10: 138 (2011)

Krokan HE, Bjerve KS, and Mork E. “The enteral bioavailability of eicosapentaenoic acid and docosahexaenoic acid is as good from ethyl esters as from glyceryl esters in spite of lower hydrolytic rates by pancreatic lipase in vitro.” Biochim Biophys Acta 1168: 59–67 (1993)

Kuipers RS, Luxwolda MF, Dijck-Brouwer DA, Eaton SB, Crawford MA, Cordain L, and Muskiet FA. “Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet.” Br J Nutr 104: 1666–1687 (2010)

Lebbadi M, Julien C, Phivilay A, Tremblay C, Emond V, Kang JX, and Calon “Endogenous conversion of omega-6 into omega-3 fatty acids improve neuropathology in an animal model of Alzheimer’s disease.” J Alzheimers Dis 27: 853–869 (2011)

Li J, Li FR, Wei D, Jia W, Kang JX, Stefanovic-Racic M, Dai Y, and Zhao AZ. “Endogenous n-3 polyunsaturated fatty acid production confers resistance to obesity, dyslipidisemia, and diabetes in mice.” Mol Endocrinol 28: 1316–1328 (2014)

Mason JE, Cook NR, Lee I-M, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D’Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, and Burning JE. “Marine n-3 fatty acids and prevention of cardiovascular disease and cancer.” N Engl J Med 380: 23–32 (2019)

Mayer K, Kiessling A, Ott J, Schaefer MB, Hecker M, Henneke I, Schulz R, Günther A, Wang J, Wu L, Roth J, Seeger W, and Kang JX. “Acute lung injury is reduced in fat-1 mice endogenously synthesizing n-3 fatty acids.” Am J Respir Crit Care Med 179: 474–483 (2009)

McNamara RK, Perry M, and Sears, B. “Dissociation of C-reactive protein levels from long-chain omega-3 fatty acid status and anti-depressant response in adolescents with major depressive disorder: An open-label dose-ranging trial.” J Nutr Therapeutics 2: 235–243 (2013)

Nordoy A, Barstad L, Connor WE, and Hatcher L. “Absorption of the n-3 eicosapentaenoic and docosahexaenoic acids as ethyl esters and triglycerides by humans.” Am J Clin Nutr 53: 1185–1190 (1991)

Norris PC, Skulas-Ray AC, Riley I, Richter CK, Kris-Etherton PM, Jensen GL, Serhan CN, and Maddipati KR. “Identification of specialized pro-resolving mediator clusters from healthy adults after intravenous low-dose endotoxin and omega-3 supplementation: A methodological validation.” Sci Rep 8: 18050 (2018)

Papanikolaou Y, Brooks J, Reider C, and Fulgoni VL. “U.S. adults are not meeting recommended levels for fish and omega-3 fatty acid intake: Results of an analysis using observational data from NHANES 2003-2008.” Nutr J 13: 31 (2014) 

Pelikanova T, Kohout M, Base J, Stefka Z, Kovar J, Kazdova L, and Valek J. “Effect of acute hyperinsulinemia on fatty acid composition of serum lipids in non- insulin-dependent diabetics and healthy men.” Clin Chim Acta 203: 329–337 (1991)

Picado C. “Mechanisms of aspirin sensitivity.” Curr Allergy Asthma Rep 6: 198–202 (2006)

Rawshani A, Sattar N, Franzén S, Rawshani A, Hattersley AT, Svensson A-M, and Eliasson B. “Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: A nationwide, register-based cohort study.” Lancet 392: 477–486 (2018)

Reis GJ, Silverman DI, Boucher TM, Sipperly ME, Horowitz GL, Sacks FM, and Pasternak RC. “Effects of two types of fish oil supplements on serum lipids and plasma phospholipid fatty acids in coronary artery disease.” Am J Cardiol 66: 1171–1175 (1990)

Rita C ed. Eicosanoids, Inflammation and Chronic Inflammatory Diseases: Pathophysiology, Health Effects and Targets for Therapies. Nova New Science (2015)

Romanatto T, Fiamoncini J, Wang B, Curi R, and Kang JX. “Elevated tissue omega-3 fatty acid status prevents age-related glucose intolerance in fat-1 transgenic mice.” Biochim Biophys Acta 1842: 186–191 (2014)

Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, McManus K, Champagne CM, Bishop LM, Laranjo N, Leboff MS, Rood JC, de Jonge L, Greenway FL, Loria CM, Obarzanek E, and Williamson DA. “Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates.” N Engl J Med 360: 859–873 (2009)

Salem N and Kuratko CN. “A reexamination of krill oil bioavailability studies.” Lipids Health Dis 13: 137 (2014)

Sears B. The Zone. Regan Books. New York, NY (1995)

Sears B. The OmegaRx Zone. Regan Books. New York, NY (2001)

Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005)

Sears B, Bailes J, and Asselin B. “Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury.” PharmaNutrition 1: 86–89 (2013)

Sears B. “High-dose omega-3 fatty acids and vitamin D for preservation of residual beta cell mass in type 1 diabetes.” CellR4 4: e2107 (2016)

See VHL, Mas E, Prescott SL, Beilin LJ, Burrows S, Barden AE, Huang RC, and Mori TA. “Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: A double-blind, randomised controlled clinical trial.” Br J Nutr 118: 971–980 (2017)

Serhan CN. “Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): A jungle of cell-cell interactions or a therapeutic opportunity?” Prostaglandins 53: 107–137 (1997)

Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O’Neill LA, Perretti M, Rossi AG, and Wallace JL. “Resolution of inflammation: State of the art, definitions and terms.” FASEB J 21: 325–332 (2007)

Serhan CN. “Treating inflammation and infection in the 21st century: New hints from decoding resolution mediators and mechanisms.” FASEB 31: 1273–1288 (2017)

Serhan CN, Chiang N, and Dalli J. “The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution.” Semin Immunol 27: 200– 215 (2015)

Serhan CN. “Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology.” Mol Aspects Med 58: 1–11 (2017)

Sorgi PJ, Hallowell EM, Hutchins HL, and Sears B. “Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder.” Nutr J 6: 16 (2007)

Spite M, Claria J, and Serhan CN. “Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases.” Cell Metab 19:21–36 (2014)

Spite M and Serhan CN. “Novel lipid mediators promote resolution of acute inflammation: Impact of aspirin and statins.” Circ Res 107: 1170–84 (2010)

Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, and Salem N. “Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults.” Prog Lipid Res 63: 132–152 (2016)

Umhau JC, Zhou W, Carson RE, Rapoport SI, Polozova A, Demar J, Hussein N, Bhattacharjee AK, Ma K, Esposito G, Majchrzak S, Herscovitch P, Eckelman WC, Kurdziel KA, and Salem N. “Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography.” J Lipid Res 50: 1259–1268 (2009)

Visser MJ. Cold, Clear, and Deadly. Michigan State University Press. East Lansing, MI (2007)

Willis AL. Handbook of Eicosanoids. CRC Press. Boca Raton, FL (1987)

Wu K, Gao X, Shi B, Chen S, Zhou X, Li Z, Gan Y, Cui L, Kang JX, Li W, and Huang “Enriched endogenous n-3 polyunsaturated fatty acids alleviate cognitive and behavioral deficits in a mice model of Alzheimer’s disease.” Neuroscience 333: 345–355 (2016)

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis.” Lancet 369: 1090–1098 (2007)

Yurko-Mauro K, Kralovec J, Bailey-Hall E, Smeberg V, Stark JG, and Salem N. “Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study.” Lipids Health Dis 14: 99 (2015)

Zhang Z, Fulgoni VL, Kris-Etherton PM, and Mitmesser SH. “Dietary intakes of EPA and DHA omega-3 fatty acids among US childbearing-age and pregnant women: An analysis of NHANES 2001–2014.” Nutrients 10: E416 (2018)

CHAPTER 11: POLYPHENOLS: ACTIVATORS OF OUR GENES, GUARDIANS OF OUR GUT

Alvarado J, Schoenlau F, Leschot A, Salgad AM, and Vigil Portales P. “Standardized maqui berry extract significantly lowers blood glucose and improves blood lipid profile in prediabetic individuals in three-month clinical trial.” Panminerva Med 58 (3 Suppl 1):1–6 (2016)

Alvarado JL, Leschot A, Olivera-Nappa Á, Salgado AM, Rioseco H, Lyon C, and Vigil P. “Delphinidin-rich maqui berry extract lowers fasting and postprandial glycemia and insulinemia in prediabetic individuals during oral glucose tolerance tests.” Biomed Res Int 2016: 9070537 (2016)

Anhe FF, Pilon G, Roy D, Desjardins Y, Levy E, and Marette A. “Triggering Akkermansia with dietary polyphenols: A new weapon to combat the metabolic syndrome?” Gut Microbes 7:146–153 (2016)

Aragonès G, Suárez M, Ardid-Ruiz A, Vinaixa M, Rodríguez MA, Correig X, Arola L, and Bladé C. “Dietary proanthocyanidins boost hepatic NAD(+) metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats.” Sci Rep 6: 24977 (2016)

Aune D, Giovannucci E, Boffetta P, Fadnes LT, Keum N, Norat T, Greenwood DC, Riboli E, Vatten LJ, and Tonstad S. “Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies.” Int J Epidemiol 46: 1029–1056 (2017)

Ayissi VB, Ebrahimi A, and Schluesenner H. “Epigenetic effects of natural polyphenols: A focus on SIRT1-mediated mechanisms.” Mol Nutr Food Res 58: 22–32 (2014)

Bao Y, Han J, Hu FB, Giovannucci EL, Stampfer MJ, Willett WC, and Fuchs SC. “Association of nut consumption with total and cause-specific mortality.” N Engl J Med 369: 2001–2011 (2013)

Basu A, Du M, Leyva MJ, Sanchez K, Betts NM, Wu M, Aston CE, and Lyons TJ. “Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome.” J Nutr 140: 1582–1587 (2010)

Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, and Small SA. “Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults.” Nat Neurosci 17: 1798–1803 (2014)

Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, and Burcelin “Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.” Diabetes 57:1470–1881(2008)

Cardona F, Andres-Lacueva C, Tulipani S, Tinahones FJ, and Queipo-Ortuno MI. “Benefits of polyphenols on gut microbiota and implications in human health.” J Nutr Biochem 24: 1415–1422 (2013)

Cárdeno A, Sánchez-Hidalgo M, Aparicio-Soto M, Sánchez-Fidalgo S, and Alarcón- de-la-Lastra C. “Extra virgin olive oil polyphenolic extracts downregulate inflammatory responses in LPS-activated murine peritoneal macrophages suppressing NF-κB and MAPK signalling pathways.” Food Funct 5: 1270–1277 (2014)

Cassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH and EB. “High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women.” Circulation 127: 188–196 (2013)

Cheng A, Han C, Fang X, Sun J, Chen X, and Wan F. “Extractable and non- extractable polyphenols from blueberries modulate LPS-induced expression of iNOS and COX-2 in RAW264.7 macrophages via the NF-κB signalling pathway.” J Sci Food Agric 96: 3393–3400 (2016)

Chu AJ. “Antagonism by bioactive polyphenols against inflammation: A systematic view.” Inflamm Allergy Drug Targets 13: 34–64 (2014)

Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, and Rahman I. “Regulation of SIRT1 in cellular functions: Role of polyphenols.” Arch Biochem Biophys 501: 79–90 (2010)

Coughlan KA, Balon TW, Valentine RJ, Petrocelli R, Schultz V, Brandon A, Cooney GJ, Kraegen EW, Ruderman NB, and Saha AK. “Nutrient excess and AMPK downregulation in incubated skeletal muscle and muscle of gluose-infused rats.” PLOS One 10: e012388 (2015)

Dasguta B and Mibrandt J. “Resveratrol stimulates AMP kinase activity in neurons.” Proc Nat Acad Sci USA 104: 7217–7222 (2007)

Davinelli S, Sapere N, Visentin M, Zella D, and Scapagnini G. “Enhancement of mitochondrial biogenesis with polyphenols: Combined effects of resveratrol and equol in human endothelial cells.” Immun Ageing 10: 28 (2013)

Davinelli S, Bertoglio JC, Zarrelli A, Pina R, and Scapagnini G. “A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract on oxidative stress biomarkers.” J Am Coll Nutr 34 Suppl 1:28–33 (2015)

Davinelli S, Corbi G, Righetti S, Sears B, Olarte HH, Grassi D, and Scapagnini G. “Cardioprotection by cocoa polyphenols and omega-3 fatty acids: A disease- prevention perspective on aging-associated cardiovascular risk.” J Med Food 21: 1–10 (2018)

Davison K, Coates AM, Buckley JD, and Howe PR. “Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects.” Int J Obesity 32: 1289–1296 (2008)

Donaldson IJ and Göttgens B. “Evolution of candidate transcriptional regulatory motifs since the human-chimpanzee divergence.” Genome Biol 7: R52 (2006)

Erlank H, Elmann A, Kohen R, and Kanner J. “Polyphenols activate Nrf2 in astrocytes via H2O2, semiquinones, and quinones.” Free Radic Biol Med 51: 2319–27 (2011)

Ford RJ, Desjardins EM, and Steinberg GR. “Are SIRTI activators another indirect method to increase AMPK for benefitical effects on aging and metabolic syndrome?” EBioMedicine 19: 16–17 (2017)

Gambelli L and Santaroni GP. “Polyphenols content in some Italian red wines of different geographical origins.” Journal of Food Composition and Analysis. 17: 613–618 (2004)

Gijsbers L, van Eekelen HD, de Haan LH, Swier JM, Heijink NL, Kloet SK, Man HY, Bovy AG, Keijer J, Aarts JM, van der Burg B, and Rietjens IM. “Induction of peroxisome proliferator-activated receptor ƴ (PPARƴ)-mediated gene expression by tomato (Solanum lycopersicum L.) extracts.” J Agric Food Chem 61: 3419– 3427 (2013)

Gilad Y, Oshlack A, Smyth GK, Speed TP, and White KP. “Expression profiling in primates reveals a rapid evolution of human transcription factors.” Nature 440: 242–245 (2006)

Hardie DG, Ross FA, and Hawley SA. “AMPK: A nutrient and energy sensor that maintains energy homeostasis.” Nat Rev Mol Cell Biol 13: 251–262 (2012)

Hardie DG. “Keeping the home fires burning: AMP-activated protein kinase.” J Royal Society Interface. 15: 20170774 (2018)

Herman WH, Pan Q, Edelstein SL, Mather KJ, Perreault L, Barrett-Connor E, Dabelea DM, Horton E, Kahn SE, Knowler WC, Lorenzo C, Pi-Sunyer X, Venditti E, and Ye W. “Impact of lifestyle and metformin interventions on the risk of progression to diabetes and regression to normal glucose regulation in overweight or obese people with impaired glucose regulation.” Diabetes Care 40: 1668–1677 (2017)

Hidalgo J, Flores C, Hidalgo MA, Perez M, Yanez A, Quinones L, Caceres DD, and Burgos RA. “Delphinol standardized maqui berry extract reduces postprandial blood glucose increase in individuals with impaired glucose regulation by novel mechanism of sodium glucose cotransporter inhibition.” Panminerva Med 56:1–7 (2014)

Huber B, Eberl L, Feucht W, and Polster J. “Influence of polyphenols on bacterial biofilm formation and quorum-sensing.” Z Naturforsch C 58: 879–884 (2003)

Hwang JT, Kwon DY, and Yoon SH. “AMP-activated protein kinase: A potential target for the diseases prevention by natural occurring polyphenols.” N Biotechnol 26: 17–22 (2009)

Hybertson BM, Gao B, Bose SK, and McCord JM. “Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation.” Mol Aspects Med 32: 234–246 (2011)

Know, L. Life: The Epic Story of Our Mitochondria. Friesen Press. Victoria, BC, Canada. (2014)

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, and Nathan DM. “Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.” N Engl J Med 346: 393–403 (2002)

Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, and Joseph JA. “Blueberry supplementation improves memory in older adults.” J Agric Food Chem 58:3996–4000 (2010)

Kulkari SS and Canto C. “The molecular targets of resveratrol.” Biochim Biophys Acta 1852: 1114–1123 (2015)

Lambert K, Hokayem M, Thomas C, Fabre O, Cassan C, Bourret A, Bernex F, Feuillet-Coudray C, Notarnicola C, Mercier J, Avignon A, and Bisbal C. “Combination of nutritional polyphenols supplementation with exercise training counteracts insulin resistance and improve endurance in high-fat diet- induced obese rats.” Sci Rep 8: 2885 (2018)

Landete JM. “Updated knowledge about polyphenols: Functions, bioavailability, metabolism, and health.” Crit Rev Food Sci Nutr 52: 936–948 (2012)

Lane N. Power, Sex, and Suicide: Mitochondria and the Meaning of Life. Oxford University Press. Oxford, UK (2005)

Lewis KN, Wason E, Edrey YH, Kristan DM, Nevo E, and Buffenstein R. “Regulation of Nrf2 signaling and longevity in naturally long-lived rodents.” Proc Natl Acad Sci U S A 112: 3722–3727 (2015)

Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, and Kong AN. “Activation of Nrf2- antioxidant signaling attenuates NF-κB-inflammatory response and elicits apoptosis.” Biochem Pharmacol 76: 1485–1489 (2008)

Manoharan I, Suryawanshi A, Hong Y, Ranganathan P, Shanmugam A, Ahmad S, Swafford D, Manicassamy B, Ramesh G, Koni PA, Thangaraju M, and Manicassamy S. “Homeostatic PPARƴ signaling limits inflammatory responses to commensal microbiota in the intestine.” J Immunol 196: 4739–4749 (2016)

Matsumoto H, Inaba H, Kishi M, Tominaga S, Hirayama M, and Tsuda T. “Orally administered delphinidin 3-rutinoside and cyanidin 3-rutinoside are directly absorbed in rats and humans and appear in the blood as the intact forms.” J Agric Food Chem 49: 1546–1551 (2001)

Menzies KJ, Singh K, Saleem A, and Hood DA. “Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis.” J Biol Chem 288: 6968– 6979 (2013)

Nowick K, Gernat T, Almaas E, and Stubbs L. “Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain.” Proc Natl Acad Sci U S A 106: 22358–22363 (2009)

Ozdal T, Sela DA, Xiao J, Boyacioglu D, Chen F, and Capanoglu E. “The reciprocal interactions between polyphenols and gut microbiota and effects on bioaccessibility.” Nutrients 8:2-36 (2016) 

Perdomo-Sabogal A, Kanton S, Walter MB, and Nowick K. “The role of gene regulatory factors in the evolutionary history of humans.” Curr Opin Genet Dev 29: 60–67 (2014)

Rabassa M, Zamora-Ros R, Andres-Lacueva C, Urpi-Sarda M, Bandinelli S, Ferrucci L and Cherubini A. “Association between both total baseline urinary and dietary polyphenols and substantial physical performance decline risk in older adults: A 9-year follow-up of the InCHIANTI Study.” J Nutr Health Aging 20: 478–485 (2016)

Rivera-Chávez F, Zhang LF, Faber F, Lopez CA, Byndloss MX, Olsan EE, Xu G, Velazquez EM, Lebrilla CB, Winter SE, and Bäumler AJ. “Depletion of butyrate-producing clostridia from the gut microbiota drives an aerobic luminal expansion of Salmonella.” Cell Host Microbe 19: 443–454 (2016)

Roopchand DE, Carmody RN, Kuhn P, Moskal K, Rojas-Silva P, Turnbaugh PJ, and Raskin I. “Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome.” Diabetes 64: 2847–2858 (2015)

Scalbert A, Johnson IT, and Saltmarsh M. “Polyphenols: Antioxidants and beyond.” Am J Clin Nutr 81: 215S–217S (2005)

Scapagnini G, Vasto S, Abraham NG, Caruso C, Zella D, and Fabio G. “Modulation of Nrf2/ARE pathway by food polyphenols: A nutritional neuroprotective strategy for cognitive and neurodegenerative disorders.” Mol Neurobiol 44: 192–201 (2011)

Scazzocchio B, Varì R, Filesi C, D’Archivio M, Santangelo C, Giovannini C, Iacovelli A, Silecchia G, Li Volti G, Galvano F, and Masella R. “Cyanidin-3-O- β-glucoside and protocatechuic acid exert insulin-like effects by upregulating PPARγ activity in human omental adipocytes.” Diabetes 60: 2234–2244 (2011)

Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, Gomis R, Claret M, and Cani PD. “Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice.” Sci Rep 13: 16643 (2015)

Schottker B, Saum KU, Jansen EH, Boffetta P, Trichopoulou A, Holleczek B, Dieffenbach AK, and Brenner H. “Oxidative stress markers and all-cause mortality at older age: A population-based cohort study.” J Gerontol A Biol Sci Med Sci 70: 518–24 (2015)

Sears B and Ricordi C. “Role of fatty acids and polyphenols in inflammatory gene transcription and their impact on obesity, metabolic syndrome, and diabetes.” Eur Rev Med Pharmacol Sci 16: 1137–1154 (2012)

Sears B. The Mediterranean Zone. Ballantine Books. New York, NY (2014)

Sears B. “Polyphenols: Novel applications in human health.” CellR4 5: e2437 (2017)

Serra D, Almeida LM, and Dinis TC. “Anti-inflammatory protection afforded by cyanidin-3-glucoside and resveratrol in human intestinal cells via Nrf2 and PPAR-ƴ: Comparison with 5-aminosalicylic acid.” Chem Biol Interact 260: 102–109 (2016)

Slobodníková L, Fialova S, Rendekova K, Kovac, and Mucaji P. “Antibiofilm activity of plant polyphenols.” Molecules 21: E1717 (2016)

Solano C, Echeverz M, and Lasa I. “Biofilm dispersion and quorum sensing.” Curr Opin Microbiol 18: 96–104 (2014)

Smith BK and Steinberg GR. “AMP-activated protein kinase, fatty acid, metabolism, and insulin sensitivity.” Curr Opin Clin Nutr Metab Care 20: 248–253 (2017)

Urpi-Sarda M, Andres-Lacueva C, Rabassa M, Ruggiero C, Zamora-Ros R, Bandinelli S, Ferrucci L, and Cherubini A. “The relationship between urinary total polyphenols and the frailty phenotype in a community-dwelling older population: The InCHIANTI study.” J Gerontol A Biol Sci Med Sci 70: 1141– 1147 (2015)

Zamora-Ros R, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, and Andres-Lacueva C. “High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults.” J Nutr 143: 1445–1450 (2013)

Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, and Cohen RA. “Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL- receptor-deficient mice.” Diabetes 55: 2180–2191 (2006)

CHAPTER 12: PERSONALIZING THE ZONE PRO-RESOLUTION NUTRITION SYSTEM

Beglinger C, and Degen L. “Fat in the intestine as a regulator of appetite—role of CCK.” Physiol Behav 83: 617–621 (2004)

Cai Z, Xiao M, Chang L, and Yan LJ. “Role of insulin resistance in Alzheimer’s disease.” Metab Brain Dis 30: 839–851 (2015)

De Silva A and Bloom SR. “Gut hormones and appetite control: A focus on PYY and GLP-1 as therapeutic targets in obesity.” Gut Liver 6: 10–20 (2012)

Duda-Chodak A, Tarko T, Satora P, and Sroka P. “Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota.” Eur J Nutr 54: 325–341 (2015)

Holst JJ. “Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery.” Int J Obes 40:1699–1706 (2016)

Johnson CS, Sears B, Perry M, and Knurick JR. “Use of novel high-protein functional food products as part of a calorie-restricted diet to reduce insulin resistance and increase lean body mass in adults: A randomized controlled trial.” Nutrients 9: 1182 (2017)

Kim J, Chae YK, and Chernoff A. “The risk for coronary heart disease according to insulin resistance with and without type 2 diabetes.” Endocr Res 38: 195–205 (2013)

le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos A, Laurenius A, Lönroth H, Fändriks L, Ghatei MA, Bloom SR, and Olbers T. “Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass.” Ann Surg 246: 780–785 (2007)

Léveillé P, Chouinard-Watkins R, Windust A, Lawrence P, Cunnane SC, Brenna JT, and Plourde M. “Metabolism of uniformly labeled 13C-eicosapentaenoic acid and 13C-arachidonic acid in young and old men.” Am J Clin Nutr 106: 467–474 (2017)

Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, and Roberts SB. “High glycemic index foods, overeating, and obesity.” Pediatrics 103: E26 (1999)

Markovic TP, Jenkins AB, Campbell LV, Furler SM, Kraegen EW, and Chisholm DJ. “The determinants of glycemic responses to diet restriction and weight loss in obesity and NIDDM.” Diabetes Care 21: 687–694 (1998)

McLaughlin T, Allison G, Abbasi F, Lamendola C, and Reaven G. “Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals.” Metabolism 53: 495–499 (2004)

Ostman EM, Liljeberg Elmståhl HG, and Björck IM. “Inconsistency between glycemic and insulinemic responses to regular and fermented milk products.” Am J Clin Nutr 74: 96–100 (2001)

Reaven GM. “Relationships among insulin resistance, type 2 diabetes, essential hypertension, and cardiovascular disease: similarities and differences.” J Clin Hypertens 13: 238–243 (2011)

Reaven G. “Insulin resistance and coronary heart disease in nondiabetic individuals.” Arterioscler Thromb Vasc Biol 32: 1754–1759 (2012)

Rubio L, Macia A, and Motilva MJ. “Impact of various factors on pharmacokinetics of bioactive polyphenols: An overview.” Curr Drug Metab 5: 62–76 (2014)

Sears B. The Zone. Regan Books. New York, NY (1995)

Sears B. Mastering the Zone. Regan Books. New York, NY (1997)

Sears B. Zone Perfect Meals in Minutes. Regan Books. New York, NY (1997)

Sears B. Zone Food Blocks. Regan Books. New York, NY (1998)

Sears B. 100 Great Zone Foods. Regan Books. New York, NY (2001)

Sears B. What to Eat in the Zone. Regan Books. New York, NY (2003)

Sears L and Sears B. Zone Meals in Seconds. Regan Books. New York, NY (2004)

Sears B and Perry M. “The role of fatty acids in insulin resistance.” Lipids Health Disease 14: 121 (2015) 

Sharon G, Garg N, Debelius J, Knight R, Dorrestein PC, and Mazmanian SK. “Specialized metabolites from the microbiome in health and disease.” Cell Metab 20: 719–730 (2014)

Svane MS, Jørgensen NB, Bojsen-Møller KN, Dirksen C, Nielsen S, Kristiansen VB, Toräng S, Wewer Albrechtsen N, Rehfeld JF, Hartmann B, Madsbad S, Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, and Arnold SE. “Demonstrated brain insulin resistance

in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.” J Clin Invest 122: 1316–1338 (2012)

Umhau JC, Zhou W, Carson RE, Rapoport SI, Polozova A, Demar J, Hussein N, Bhattacharjee AK, Ma K, Esposito G, Majchrzak S, Herscovitch P, Eckelman WC, Kurdziel KA, and Salem N Jr. “Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography.” J Lipid Res 50: 1259–1268 (2009)

Verdile G, Keane KN, Cruzat VF, Medic S, Sabale M, Rowles J, Wijesekara N, Martins RN, Fraser PE, and Newsholme P. “Inflammation and oxidative stress: The molecular connectivity between insulin resistance, obesity, and Alzheimer’s disease.” Mediators Inflamm 2015: 105828 (2015)

Wickremesekera K, Miller G, Naotunne TD, Knowles G, and Stubbs RS. “Loss of insulin resistance after Roux-en-Y gastric bypass surgery: A time course study.” Obes Surg 15: 474–481 (2005)

Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, and Clinton SK. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91: 1185–1194 (2010)

CHAPTER 13: DIET FACTS AND FALLACIES

Arnardottir H, Orr SK, Dalli J, and Serhan CN. “Human milk proresolving mediators stimulate resolution of acute inflammation.” Mucosal Immunol 9: 757-766 (2016)

Appleby PN, Crowe FL, Bradbury KE, Tavis RC, and Key TJ. “Mortality in vegetarians and comparable nonvegetarians in the United Kingdom.” Am J Clin Nutr 103: 218–230 (2016)

Bao J, de Jong V, Atkinson F, Petocz P, and Brand-Miller JC. “Food insulin index: Physiologic basis for predicting insulin demand evoked by composite meals.” Am J Clin Nutr 90: 986–992 (2009)

Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, and Gibson PR. “No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.” Gastroenterology 145: 320–328 (2013)

Blaser MJ. “The theory of disappearing microbiota and the epidemics of chronic disease.” Nat Rev 17: 461–463 (2017)

Boudry G, Hamilton MK, Chicholwski M, Wichramasinghe S, Barile D, Kalaneta KM, Mills DA, and Raybould HE. “Bovine milk oligosaccharides decrease gut permeability and improve inflammation and microbial dysbosis in diet-induced obese mice.” J Dairy Sci 100:2471–2481 (2017)

Burger J, Kirchner M, Bramanti B, Haak W, and Thomas MG. “Absence of the lactase-persistence-associated allele in early Neolithic Europeans.” Proc Nat Acad Sci USA 104: 3736–3741 (2007)

Cabrera G, Fernández-Brando RJ, Mejías MP, Ramos MV, Abrey-Recalde MJ, Vanzulli S, Vermeulen M, and Palermo MS. “Leukotriene C4 increases the susceptibility of adult mice to Shiga toxin-producing Escherichia coli infection.” Int J Med Microbiol 305: 910–917 (2015)

Carden TJ and Carr TP. “Food availability of glucose and fat, but not fructose, increased in the U.S. between 1970 and 2009: Analysis of the USDA food availability data system.” Nutr J 12: 130 (2013)

Cargnello M, Tcherkezian J, and Roux PP. “The expanding role of mTOR in cancer cell growth and proliferation.” Mutagenesis 30: 169–176 (2015)

Chiarini F, Evangelisti C, McCubrey JA, and Martelli AM. “Current treatment strategies for inhibiting mTOR in cancer.” Trends Pharmacol Sci 36: 124–135 (2015).

Cohen DH and LeRoith D. “Obesity, type 2 diabetes, and cancer: The insulin and IGF connection.” Endocr Relat Cancer 19: F27–45 (2012)

Cozma AI, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Wang DD, Mirrahimi A, Yu ME, Carleton AJ, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Beyene J, Kendall CW, and Jenkins DJ. “Effect of fructose on glycemic control in diabetes: A systematic review and meta-analysis of controlled feeding trials.” Diabetes Care 35: 1611–1620 (2012)

Dong Z, Zhou S, and Mechef Y. “LC-MS/MS analysis of permethylated free oligosaccharides and N-glycans derived from human, bovine, and goat milk samples.” Electrophoresis 37: 1532–1548 (2016)

Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D’Agate C, Not T, Zampini L, Catassi C, and Fasano A. “Gliadin, zonulin and gut permeability: Effects on celiac and non- celiac intestinal mucosa and intestinal cell lines.” Scand J Gastroenterol 41: 408–419 (2006)

GBD 2016 Alcohol Collaborators. “Alcohol use and burden for 195 countries and territories, 1990-2016: A systematic analysis for the Global Burden of Disease study 2016.” Lancet 392: 1015–1035 (2018)

Gerbault P, Libert A, Itan Y, Powell A, Currat M, and Burger J. “Evolution of lactose persistence: An example of human niche construction.” Phil Trans Royal Soc B 366: 863–877 (2011) 

Hamilton MK, Ronveaux CC, Rust BM, Newman JW, Hawley M, Barile D, and Raybould HE. “Prebiotic milk oligosaccharides prevent the development of obese phenotype, impairment of gut permeability, and microbial dysbiosis in high-fat fed mice.” Am J Physiol Gastrointest Liver Physiol 312: G474–G487 (2017)

Hardie DG, Ross FA, and Hawley SA. “AMP-activate protein kinase: A target for drugs both ancient and modern.” Chem Bio 19: 1222–1236 (2012)

Hokayem M, Blond E, Vidal H, Lambert K, Meugnier E, Feillet-Coudray C, Coudray C, Pesenti S, Luyton C, Lambert-Porcheron S, Sauvinet V, Fedou C, Brun JF, Rieusset J, Bisbal C, Sultan A, Mercier J, Goudable J, Dupuy AM, Cristol JP, Laville M, and Avignon A. “Grape polyphenols prevent fructose- induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients.” Diabetes Care 36: 1454–1461 (2013)

Hwang DH, Kim JA, and Lee JY. “Mechanisms for the activation of Toll-like receptor 2/4 by saturated fatty acids and inhibition by docosahexaenoic acid.” Eur J Pharmacol 785: 24–35 (2016)

Institute of Medicine: Dietary Reference Intakes: Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC, National Academies Press. (2002)

Itan Y, Powell A, Beaumont MA, Burger J, and Thomas MG. “The origin of lactase persistence in the Europe.” PLoS Comput Biol 5: e1000491 (2009)

Jang C, Hui S, Lu W, Cowan AJ, Morscher RJ, Lee G, Liu W, Tesz GJ, Birnbaum MJ, and Rabinowitz JD. “The small intestine converts dietary fructose into glucose and organic acids.” Cell Metab 27: 351–361 (2018)

Kendall CW, and Jenkins DJ. “Effect of fructose on postprandial triglycerides: A systematic review and meta-analysis of controlled feeding trials.” Atherosclerosis 232: 125–133 (2014)

Kolberg J and Sollid L. “Lectin activity of gluten identified as wheat germ agglutinin.” Biochem Biophys Res Commun 130: 867–872 (1985)

Kretchmer N. “Expression of lactase during development.” Am J Human Genet 45: 487–488 (1989)

Kunz C and Rudloff S. “Potential anti-inflammatory and anti-infectious effects of human milk oligosaccharides.” Adv Exp Med Bio 606: 455–465 (2006)

Levinovitz A. The Gluten Lie. Regan Arts. New York, NY (2015)

Li F, Yin Y, Tan B, Kong X, and Wu G. “Leucine nutrition in animals and humans: mTOR signaling and beyond.” Amino Acids 41: 1185–1193 (2011)

Lowndes J, Kawiecki D, Pardo S, Nguyen V, Melanson KJ, Yu Z, and Rippe JM. “The effects of four hypocaloric diets containing different levels of sucrose or high fructose corn syrup on weight loss and related parameters.” Nutr J 11: 55 (2012)

Marriott BP, Cole N, and Lee E. “National estimates of dietary fructose intake from 1977 to 2004 in the United States.” J Nutrition 139: 1228S–1235S (2009)

Mehra R, Sarie D, Marotta M, Lebrille CB, Chu C, and German JB. “Novel high-molecular weight fucosylated milk oligosaccharides identified in dairy streams.” PLoS One 9: e96040 (2014)

Mihrshahi S, Ding D, Gale J, Allman-Farinelli M, Banks E, and Bauman AE. “Vegetarian diet and all-cause mortality: Evidence from a large population- based Australian cohort-the 45 and Up Study.” Preventive Medicine 97: 1–7 (2017)

Murry RD, Ailaboui AH, Powers PA McClung HJ, Li Bu, Heitlinger LA, and Sloan HR. “Absorption of lactose from the colon of the newborn piglet.” Am J Physiol 261: G1–8 (1991)

Orlich MJ, Singh PN, Sabate J, Kaceido-Siegl K, Fan J, Knutsen S Beeson L, and Fraser GE. “Vegetarian dietary plans and mortality in Adventist Health Study 2.” JAMA Intern Med 173: 1230–1238 (2013)

Ostman EM, Liljeberg Elmståhl HG, and Björck IM. “Inconsistency between glycemic and insulinemic responses to regular and fermented milk products.” Am J Clin Nutr 74: 96–100 (2001)

Owen OE, Felig P, Morgan AP, Wahren J, and Cahill GF. “Liver and kidney metabolism during prolonged starvation.” J Clin Invest 48: 574–583 (1969)

Peng L, Li ZR, Green RS, Holzman IR, and Lin J. “Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers.” J Nutr 139: 1619–1625 (2009)

Plöger S, Stumpff F, Penner GB, Schulzke JD, Gäbel G, Martens H, Shen Z, Günzel D, and Aschenbach JR. “Microbial butyrate and its role for barrier function in the gastrointestinal tract.” Ann N Y Acad Sci 1258: 52–59 (2012)

Qin LQ, He K, and Xu JY. “Milk consumption and circulating insulin-like growth factor-I level: A systematic literature review.” Int J Food Sci Nutr 60 (Suppl 7): 330–340 (2009)

Sears B. The Anti-Aging Zone. Regan Books. New York, NY (1999)

Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)

Sievenpiper JL, de Souza RJ, Mirrahimi A, Yu ME, Carleton AJ, Beyene J, Chiavaroli L, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Kendall CW, and Jenkins DJ. “Effect of fructose on body weight in controlled feeding trials: A systematic review and meta-analysis.” Ann Intern Med 156: 291–304 (2012)

Siri-Tarino PW, Sun Q, Hu FB, and Krauss RM. “Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease.” Am J Clin Nutr 91: 535–546 (2010)

Stahel P, Kim JJ, Xiao C, and Cant JP. “Of milk the sugars, galactose, but not prebiotic galacto-oligoscaccharide, improves insulin sensitivity in male Sprague- Dawley rats.” PLoS 12: e0172260 (2017)

Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, and Elinav E. “Artificial sweeteners induce glucose intolerance by altering the gut microbiota.” Nature 514: 181–186 (2014)

Tome D. “Criteria and markers for protein quality assessment – a review.” Br J Nutr 108 (Suppl 2): S222–229 (2012)

Troelsen JT. “Adult-type hypolactasia and regulation of lactase expression.” Biochim Biophys Acta 1723: 19–32 (2005)

Topiwala A, All CL, Valkanova V, Zsoldos E, Filippini N, Sexton C, Mahmood A, Fooks P, Signh-Manoux A, Mackay CE, Kivimaki M, and Ebeier KP. “Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline.” BMJ 357: 2353 (2017)

Wang DD, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Cozma AI, Mirrahimi A, Yu ME, Carleton AJ, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Beyene J, Kendall CW, and Jenkins DJ. “The effects of fructose intake on serum uric acid vary among controlled dietary trials.” J Nutr 42: 916–923 (2012)

Wang DD, Sievenpiper JL, de Souza RJ, Cozma AI, Chiavaroli L, Ha V, Mirrahimi A, Carleton AJ, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Beyene J, Kendall CW, and Jenkins DJ. “Effect of fructose on postprandial triglycerides: A systematic review and meta-analysis of controlled feeding trials.” Atherosclerosis 232: 125–133 (2014)

Zhao J, Stockwell T, Boemer A, Naimi T, and Chikritzhs T. “Alcohol consumption and morality from coronary heart disease.” J Stud Alcohol Drugs 78: 375–386 (2017)

Zhou BR, Zhang JA, Zhang Q, Permatasari F, Xu Y, Wu D, Yin ZQ, and Luo D. “Palmitic acid induces production of proinflammatory cytokines interleukin-6, interleukin-1β, and tumor necrosis factor-α via a NF-κB-dependent mechanism in HaCaT keratinocytes.” Mediators Inflamm 2013: 530429 (2013)

Zong G, Li Y, Wanders AJ, Alssema M, Zock PL, Willett WC, Hu FB, and Sun Q. “Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: Two prospective longitudinal cohort studies.” BMJ 355: i5796 (2016)

CHAPTER 14: DIET WARS: COMPARISON OF THE ZONE DIET TO OTHER DIETS

Andrews RC and Walker BR. “Glucocorticoids and insulin resistance: Old hormones, new targets.” Clin Sci 96: 513–523 (1999)

Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM, Cutler JA, Windhauser MM, Lin PH, and Karanja N. “A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group.” N Engl J Med 336: 1117–1124 (1997)

Barnosky AR, Hoddy KK, Unterman TG, and Varady KA. “Intermittent fasting vs daily calorie restriction for type 2 diabetes prevention: A review of human findings.” Transl Res 164: 302–311 (2014)

Carter S, Clifton PM, and Keogh JB. “Effect of intermittent compared with continuous energy restricted diet on glycemic control in patients with type 2 diabetes: A randomized noninferiority trial.” JAMA Netw Open 1: e180756 (2018)

Eaton SB and Konner M. “Paleolithic nutrition. A consideration of its nature and current implications.” N Engl J Med 312: 283–289 (1985)

Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, and Ludwig DS. “Effects of dietary composition on energy expenditure during weight-loss maintenance.” JAMA 307: 2627–2634 (2012)

Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA, and Martínez-González MA. “Primary prevention of cardiovascular disease with a Mediterranean diet.” N Engl J Med 368: 1279–1290 (2013)

Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA, and Martínez-González MA. “Retraction and republication: Primary prevention of cardiovascular disease with a Mediterranean diet.” N Engl J Med 378: 2441–2442 (2018)

Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA, Fitó M, Gea A, Hernán MA, and Martínez-González MA. “Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts.” N Engl J Med 378:e34 (2018)

Geer EB, Islam J, and Buettner C. “Mechanisms of glucocorticoid-induced insulin resistance: Focus on adipose tissue function and lipid metabolism.” Endocrinol Metab Clin North Am 43: 75–102 (2014)

Hall KD, Bemis T, Brychta R, Chen KY, Courville A, Crayner EJ, Goodwin S, Guo J, Howard L, Knuth ND, Miller BV 3rd, Prado CM, Siervo M, Skarulis MC, Walter M, Walter PJ, and Yannai L. “Calorie for calorie, dietary fat restriction results in more body fat loss than carbohydrate restriction in people with obesity.” Cell Metab 22: 427–436 (2015)

Giusti J and Rizzott J. “Interpreting the Joslin Diabetes Center and Joslin Clinic clinical guideline for overweight and obese adults with type 2 diabetes.” Curr Diab Report 6: 405–408 (2006)

Hamdy O. “Diabetes weight management in clinical practice—the Why Wait model,” US Endocrinology 4: 49–54 (2008)

Hamdy O and Carver C. “The Why WAIT program: Improving clinical outcomes through weight management in type 2 diabetes.” Curr Diab Rep 8: 413–420 (2008)

Hamdy O, Mottalib A, Morsi A, El-Sayed N, Goebel-Fabbri A, Arathuzik G, Shahar J, Kirpitch A, and Zrebiec J. “Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: A 5-year longitudinal study.” BMJ Open Diabetes Res Care 5: e000259 (2017)

Harris L, McGarty A, Hutchison L, Ells L, and Hankey C. “Short-term intermittent energy restriction interventions for weight management: A systematic review and meta-analysis.” Obes Rev 19: 1–13 (2018)

Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, and Sears B. “Ketogenic low-carbohydrate diets have no metabolic advantage over non-ketogenic low- carbohydrate diets.” Am J Clin Nutr 83: 1055–1061 (2006)

Johnston CS, Tjonn SL, Swan PD, White A, and Sears B. “Low-carbohydrate, high-protein diets that restrict potassium-rich fruits and vegetables promote calciuria.” Osteoporos Int 17: 1820–1821 (2006)

Jornayvaz FR, Jurczak MJ, Lee HY, Birkenfeld AL, Frederick DW, Zhang D, Zhang XM, Samuel VT, and Shulman GI. “A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain.” Am J Physiol Endocrinol Metab 299: E808–815 (2010)

Khani S and Tayek JA. “Cortisol increases gluconeogenesis in humans: Its role in the metabolic syndrome.” Clin Sci 101: 739–747 (2001)

Kuipers RS, Luxwolda MF, Dijck-Brouwer DA, Eaton SB, Crawford MA, Cordain L, and Muskiet FA. “Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet.” Br J Nutr 104: 1666–1687 (2010)

Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, and Aggarwal NT. “MIND diet associated with reduced incidence of Alzheimer’s disease.” Alzheimers Dement 11: 1007–1014 (2015)

Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA, and Aggarwal NT. “MIND diet slows cognitive decline with aging.” Alzheimers Dement 11: 1015–1022 (2015)

Mosley M and Spencer M. The Fast Diet. Simon and Shuster. New York, NY (2013) Nishihira J, Tokashiki T, Higashiuesato Y, Willcox DC, Mattek N, Shinto L, Ohya

Y, and Dodge HH. “Associations between serum omega-3 fatty acid levels and cognitive functions among community-dwelling octogenarians in Okinawa, Japan: The KOCOA study.” J Alzheimers Dis 51:857–866 (2016)

Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER, Simons-Morton DG, Karanja N, and Lin PH. “Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.” N Engl J Med 344: 3–10 (2001)

Schübel R, Nattenmüller, Sookthai D, Nonnenmacher T, Graf ME, Riedl L, Schlett CL, von Stackelberg O, Johnson T, Nabers D, Kirsten R, Kratz M, Kauczor HU, Ulrich CM, Kaaks R, and Kühn T. “Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: A randomized controlled trial.” Am J Clin Nutr 108: 933–945 (2018)

Suzuki M, Willcox DC, Rosenbaum MW, and Willcox BJ. “Oxidative stress and longevity in Okinawa: An investigation of blood lipid peroxidation and tocopherol in Okinawan centenarians.” Curr Gerontol Geriatr Res. 2010:380460 (2010) 

Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, Gabel K, Freels S, Rigdon J, Rood J, Ravussin E, and Varady KA. “Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: A randomized clinical trial.” JAMA Intern Med 177: 930–938 (2017)

White AM, Johnston CS, Swan PD, Tjonn SL, and Sears B. “Blood ketones are directly related to fatigue and perceived effort during exercise in overweight adults adhering to low-carbohydrate diets for weight loss: A Pilot study.” J Am Diet Assoc 107: 1792–1796 (2007)

Willcox BJ and Willcox DG. The Okinawa Program: How the World’s Longest-Lived People Achieve Everlasting Health—And How You Can Too. Three Rivers Press. New York, NY (2001)

Willcox DC, Willcox BJ, Todoriki H, and Suzuki M. “The Okinawan diet: Health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load.” J Am Coll Nutr 28: 500S–516S (2009)

Willcox BJ and Willcox DC. “Caloric restriction, caloric restriction mimetics, and healthy aging in Okinawa: Controversies and clinical implications.” Curr Opin Clin Nutr Metab Care17: 51–58 (2014)

Willcox DC, Scapagnini G, and Willcox BJ. “Healthy aging diets other than the Mediterranean: A focus on the Okinawan diet.” Mech Ageing Dev 136-137: 148–162 (2014)

CHAPTER 15: ZONE PROTEIN: MAKING THE ZONE DIET EVEN EASIER TO FOLLOW

Chan JL, Mun EC, Stoyneva V, Mantzoros CS, and Goldfine AB. “Peptide YY levels are elevated after gastric bypass surgery.” Obesity 14: 194–198 (2006)

De Silva A and Bloom SR. “Gut hormones and appetite control: A focus on PYY and GLP-1 as therapeutic targets in obesity.” Gut Liver 6: 10–20 (2012)

Johnson CS, Sears B, Perry M, and Knurick JR. “Use of novel high-protein functional food products as part of a calorie-restricted diet to reduce insulin resistance and increase lean body mass in adults: A randomized controlled trial.” Nutrients 9:1182 (2017)

Khalaf KH and Taegtmeyer H. “Clues from bariatric surgery: Reversing insulin resistance to heal the heart.” Curr Diab Rep 13: 245–251 (2013)

Salehi M, Prigeon RL, and D’AlessioDA, “Gastric bypass surgery enhances glucagon-like peptide 1–stimulated postprandial insulin secretion in humans.” Diabetes 60: 2308–2314 (2011)

Wickremesekera K, Miller G, Naotunne TD, Knowles G, and Stubbs RS. “Loss of insulin resistance after Roux-en-Y gastric bypass surgery: A time course study.” Obes Surg 15: 474–48 (2005) 

CHAPTER 16: YOUR FIRST 1,000 DAYS AND BEYOND

Ailhaud G, Guesnet P, and Cunnane SC. “An emerging risk factor for obesity: Does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development?” Br J Nutr 100: 461–470 (2008)

Allis CD, Caparros M-L, Jenuwein T, and Reinberg D. Epigenetics. Cold Spring Harbor Laboratory Press. Cold Springs, NY (2007)

Alvheim AR, Malde MK, Osei-Hyiaman D, Lin YH, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, and Hibbeln JR. “Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity.” Obesity 20: 1984– 1994 (2012)

Alvheim AR, Torstensen BE, Lin YH, Lillefosse HH, Lock EJ, Madsen L, Frøyland L, Hibbeln JR, and Malde MK. “Dietary linoleic acid elevates the endocannabinoids 2-AG and anandamide and promotes weight gain in mice fed a low-fat diet.” Lipids 49: 59–69 (2014)

Bode L. “The functional biology of human milk oligosaccharides.” Early Hum Dev 91: 619–622 (2015)

Calvani R, Picca A, Lo Monaco MR, Landi F, Bernabei R, and Marzetti E. “Of microbes and minds: A narrative review on the second brain aging.” Front Med 5: 53 (2018)

Casey BJ, Jones RM, and Hare TA. “The adolescent brain.” Ann N Y Acad Sci 1124: 111–126 (2008)

Chalon S. “Omega-3 fatty acids and monoamine neurotransmission.” Prostaglandins Leukot Essent Fatty Acids 75: 259–69 (2006)

Catalano PM. “Trying to understand gestational diabetes.” Diabet Med 31: 273–281 (2014)

Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, Bell R, Badaru A, Talton JW, Crume T, Liese AD, Merchant AT, Lawrence JM, Reynolds K, Dolan L, Liu LL, and Hamman RF. “Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009.” JAMA 311: 1778–1786 (2014)

Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, and Knight R. “Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.” Proc Natl Acad Sci U S A 107: 11971–11975 (2010)

el Hajj N, Schneider E, Lehnen H, and Haaf T. “Epigenetics and life-long consequences of an adverse nutritional and diabetic intrauterine environment.” Reproduction 148: R111–20 (2014)

Evrensel A and Ceylan ME. “The gut-brain axis: The missing link in depression.” Clin Psychopharmacol Neurosci 13: 239–244 (2015)

Ferrazzi E and Sears B eds. Metabolic Syndrome and Complications of Pregnancy. Springer. Heidelburg, Germany (2015) 

Frye RE, Rose S, Chacko J, Wynne R, Bennuri SC, Slattery JC, Tippett M, Delhey L, Melnyk S, Kahler SG, and MacFabe DF. “Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines.” Transl Psychiatry 6: e927 (2016)

Germano M, Meleleo D, Montorfano G, Adorni L, Negroni M, Berra B, and Rizzo AM. “Plasma, red blood cells phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD).” Nutr Neurosci 10: 1–9 (2007)

Hanbauer I, Rivero-Covelo I, Maloku E, Baca A, Hu Q, Hibbeln JR, and Davis JM. “The decrease of n-3 fatty acid energy percentage in an equicaloric diet fed to B6C3Fe mice for three generations elicits obesity.” Cardiovasc Psychiatry Neurol 2009: 867041 (2009)

Jensen FE. The Teenage Brain. Harper Collins. New York, NY (2015)

Kodas E, Vancassel S, Lejeune B, Guilloteau D, and Chalon S. “Reversibility of n-3 fatty acid deficiency-induced changes in dopaminergic neurotransmission in rats: Critical role of developmental stage.” J Lipid Res 43: 1209–1219 (2002)

Lacroix M, Kina E, and Hivert MF. “Maternal/fetal determinants of insulin resistance in women during pregnancy and in offspring over life.” Curr Diab Rep 13: 238–244 (2013)

MacFabe DF. “Short-chain fatty acid fermentation products of the gut microbiome: Implications in autism spectrum disorders.” Microb Ecol Health Dis 2012: 23 (2012)

Maftei O, Whitrow MJ, Davies MJ, Giles LC, Owens JA, and Moore VM. “Maternal body size prior to pregnancy, gestational diabetes and weight gain: Associations with insulin resistance in children at 9-10 years.” Diabet Med 32: 174–180 (2015)

Massiera F, Saint-Marc P, Seydoux J, Murata T, Kobayashi T, Narumiya S, Guesnet P, Amri EZ, Negrel R, and Ailhaud G. “Arachidonic acid and prostacyclin signaling promote adipose tissue development: A human health concern?” J Lipid Res 44: 271–279 (2003)

Massiera F, Guesnet P, and Ailhaud G. “The crucial role of dietary n-6 polyunsaturated fatty acids in excessive adipose tissue development: Relationship to childhood obesity.” Nestle Nutr Workshop Ser Pediatr Program 57: 235–242 (2006)

Massiera F, Barbry P, Guesnet P, Joly A, Luquet S, Moreilhon-Brest C, Mohsen- Kanson T, Amri EZ, and Ailhaud G. “A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations.” J Lipid Res51: 2352–2361 (2010)

Mastrogiannis DS, Spiliopoulos M, Mulla W, and Homko CJ. “Insulin resistance: The possible link between gestational diabetes mellitus and hypertensive disorders of pregnancy.” Curr Diab Rep 9: 296–302 (2009)

Möhler H. “The GABA system in anxiety and depression and its therapeutic potential.” Neuropharmacology 62: 42–53 (2012)

Mojtabai R, Olfson M, and Han B. “National trends in the prevalence and treatment of depression in adolescents and young adults.” Pediatrics 138: e20161878 (2016)

Morrison JL, Duffield JA, Muhlhausler BS, Gentili S, and McMillen IC. “Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity.” Pediatr Nephrol 25: 669–677 (2010)

Mühlhäusler BS. “Programming of the appetite-regulating neural network: A link between maternal overnutrition and the programming of obesity?” J Neuroendocrinol 19: 67–72 (2007)

Muhlhausler BS and Ong ZY. “The fetal origins of obesity: Early origins of altered food intake.” Endocr Metab Immune Disord Drug Targets11: 189–197 (2011)

Muhlhausler BS and Ailhaud GP. “Omega-6 polyunsaturated fatty acids and the early origins of obesity.” Curr Opin Endocrinol Diabetes Obes 20: 56–61 (2013)

Munyaka PM, Khafipour E, and Ghia JE. “External influence of early childhood establishment of gut microbiota and subsequent health implications.” Front Pediatr 2:109 (2014)

Nordgren TM, Lyden E. Anderson-Berry A, and and Hanson C. “Omega-3 fatty acid intake of pregnant women and women of childbearing age in the United States: Potential for deficiency?” Nutrients 9: 197 (2017)

Ong ZY and Muhlhausler BS. “Maternal “junk-food” feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring.” FASEB J 25: 2167–2179 (2011)

Painter RC, de Rooij SR, Bossuyt PM, Simmers TA, Osmond C, Barker DJ, Bleker OP, and Roseboom TJ. “Early onset of coronary artery disease after prenatal exposure to the Dutch famine.” Am J Clin Nutr 84: 322–327 (2006)

Pantham P, Aye IL, and Powell TL. “Inflammation in maternal obesity and gestational diabetes mellitus.” Placenta 36: 709–715 (2015)

Poston L. “Intergenerational transmission of insulin resistance and type 2 diabetes.” Prog Biophys Mol Biol 106: 315–322 (2011)

Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, and Bleker OP. “Obesity at the age of 50 y in men and women exposed to famine prenatally.” Am J Clin Nutr 70: 811–816 (1999)

Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, and Bleker OP. “Effects of prenatal exposure to the Dutch famine on adult disease in later life: An overview.” Mol Cell Endocrinol 185: 93–98 (2001)

Shultz SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R, and Cain DP. “Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism.” Neuropharmacology 54: 901–911 (2008)

See VHL, Mas E, Prescott SL, Beilin LJ, Burrows S, Barden AE, Huang RC, and Mori TA. “Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: A double-blind, randomised controlled clinical trial.” Br J Nutr 118:971–980 (2017)

Segovia SA, Vickers MH, Gray C, and Reynolds CM. “Maternal obesity, inflammation, and developmental programming.” Biomed Res Int. 2014: 418975 (2014)

Singer K and Lumeng CN. “The initiation of metabolic inflammation in childhood obesity.” J Clin Invest 127: 65–73 (2017)

Sorgi PJ, Hallowell EM, Hutchins HL, and Sears B. “Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder.” Nutr J 6: 16 (2007)

Stewart CJ, Ajami AJ, O’Brien JL, Hutchinson DS, Smith DP, Wong MC, Ross MC, Lloyd RE, Doddapaneni HV, Metcalf GA, Muzny D, Gibbs RA, Vatanen T, Huttenhower C, Xavier RJ, Rewers M, Hagopian W, Toppari J, Ziegler A-G, She J-X, Akolkar B, Lernmark A, Hyoty H, Vehik K, Krischer JP, and Petrosino “Temporal development of the gut microbiome in early childhood from the TEDDY study.” Nature 562: 583–588 (2018)

Strandwitz P. “Neurotransmitter modulation by the gut microbiota.” Brain Res 1693(Pt B):128–133 (2018)

Tollesbol T. Transgenerational Epigenetics. Academic Press. London, UK (2014) van Dijk SJ, Peters TJ, Buckley M, Zhou J, Jones PA, Gibson RA, Makrides M, Muhlhausler BS, and Molloy PL. “DNA methylation in blood from neonatal screening cards and the association with BMI and insulin sensitivity in early childhood.” Int J Obes 42: 28–35 (2018)

Vickers MH. “Early life nutrition, epigenetics and programming of later life disease.” Nutrients 6: 2165–2178 (2014)

Weinberger AH, Gbedemah M, Martinez AM, Nash D, Galea S, and Goodwin RD. “Trends in depression prevalence in the USA from 2005 to 2015: Widening disparities in vulnerable groups.” Psychol Med 48: 1308–1315 (2018)

CHAPTER 17: REACHING PEAK PERFORMANCE

Anzalone A, Carbuhn A, Jones L, Gallop A, Smith A, Johnson P, Swearingen L, Moore C, Rimer E, McBeth J, Harris W, Kirk KM, Gable D, Askow A, Jennings W, and Oliver JM. “The omega-3 index in National Collegiate Athletic Association Division I collegiate football athletes.” J Athl Train 54: 7–11 (2019)

Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, Sjostrom SL, Szewczykowska M, Jackowska T, Dos Remedios C, Malm T, Andrä M, Jashari R, Nyengaard JR, Possnert G, Jovinge S, Druid H, and Frisén J. “Dynamics of cell generation and turnover in the human heart.” Cell 61: 1566–1575 (2015)

Bloomer RJ, Larson DE, Fisher-Wellman KH, Galpin AJ, and Schilling BK. “Effect of eicosapentaenoic and docosahexaenoic acid on resting and exercise-induced inflammatory and oxidative stress biomarkers.” Lipids Health Dis. 8: 36 (2009) 

Bruckner G, Webb P, Greenwell L, Chow C, and Richardson D. “Fish oil increase peripheral capillary blood cell velocity in humans.” Atherosclerosis 66: 237–245 (1987)

Budgett R. “Overtraining syndrome.” Br J Sports Med 24: 231–236 (1990)

Burns TW, Terry BE, Langley PE, and Robison GA. “Insulin inhibition of lipolysis of human adipocytes: The role of cyclic adenosine monophosphate.” Diabetes 28: 957–961 (1979)

Cantó C and Auwerx J. “Calorie restriction: Is AMPK a key sensor and effector?” Physiology 26: 214–224 (2011)

Casanova E, Baselga-Escudero L, Ribas-Latre A, Cedó L, Arola-Arnal A, Pinent M, Bladé C, Arola L, and Salvadó MJ. “Chronic intake of proanthocyanidins and docosahexaenoic acid improves skeletal muscle oxidative capacity in diet-obese rats.” J Nutr Biochem 25: 1003–1010 (2014)

Clark A and Mach N. “The crosstalk between the gut microbiota and mitochondria during exercise.” Front Physiol 8: 319 (2017)

Clarke SD and Jump D. “Polyunsaturated fatty acids regulate lipogenic and peroxisomal gene expression by independent mechanisms.” Prostaglandins, Leukotrienes, and Essential Fatty Acids 57: 65–69 (1997)

Clavel S, Farout L, Briand M, Briand Y, and Jouanel P. “Effect of endurance training and/or fish oil supplemented diet on cytoplasmic fatty acid binding protein in rat skeletal muscles and heart.” Eur J Appl Physiol 87: 193–201 (2002)

Constanti N and Hackney AC eds. Endocrinology of Physical Activity and Sport. Humana Press. New York, NY. (2013)

Dubé JJ, Broskey NT, Despines AA, Stefanovic-Racic M, Toledo FG, Goodpaster BH, and Amati F. “Muscle characteristics and substrate energetics in lifelong endurance athletes.” Med Sci Sports Exerc 48: 472–480 (2016)

Eguchi T, Kumagai C, Fujihara T, Takemasa T, Ozawa T, and Numata O. “Black tea high-molecular-weight polyphenol stimulates exercise training-induced improvement of endurance capacity in mouse via the link between AMPK and GLUT4.” PLoS One 8: e69480 (2013)

Ernst E, Saradeth T, and Achhammer G. “n-3 fatty acids and acute-phase proteins.” Eur J Clin Invest 21: 77–82 (1991)

Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented by omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35: 499–507 (2005)

Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, and Lodi L. “Cognitive and physiological effects of omega-3 polyunsaturated fatty acid supplementation in healthy subjects.” Eur J Clin Invest 35: 691–699 (2005)

Ghigo E, Miola C, Aimaretti G, Valente F, Procopio M, Arvat E, Yin-Zhang W, and Camanni F. “Arginine abolishes the inhibitory effect of glucose on the growth hormone response to growth hormone-releasing hormone in man.” Metabolism 41:1000–1003 (1992)

Giampieri F, Alvarez-Suarez JM, Cordero MD, Gasparrini M, Forbes-Hernandez TY, Afrin S, Santos-Buelga C, González-Paramás AM, Astolfi P, Rubini C, Zizzi A, Tulipani S, Quiles JL, Mezzetti B, and Battino M. “Strawberry consumption improves aging-associated impairments, mitochondrial biogenesis and functionality through the AMP-activated protein kinase signaling cascade.” Food Chem 234: 464–471 (2017)

Gibala M. “Molecular responses to high-intensity interval exercise.” Appl Physiol Nutr Metab 34: 428–432 (2009)

Grassi D, Desideri G, Necozione S, di Giosia P, Barnabei R, Allegaert L, Bernaert H, and Ferri C. “Cocoa consumption dose-dependently improves flow-mediated dilation and arterial stiffness decreasing blood pressure in healthy individuals.” J Hypertens 33: 294–303 (2015)

Guglielmo CG, Haunerland NH, Hochachka PW, and Williams TD. “Seasonal dynamics of flight muscle fatty acid binding proteins and catabolic enzymes in a migratory shorebird.” Amer J Physiol 282: R1405–R1413 (2002)

Guglielmo CG. “Move that fatty acid: Fuel selection and transport in migratory birds and bats.” Integr Comp Biol 50:336–345 (2010)

Guimarães-Ferreira L, Cholewa JM, Naimo MA, Zhi XI, Magagnin D, de Sá RB, Streck EL, Teixeira Tda S, and Zanchi NE. “Synergistic effects of resistance training and protein intake: Practical aspects.” Nutrition 30: 1097–1103 (2014)

Guzmán JF, Esteve H, Pablos C, Pablos A, Blasco C, and Villegas JA. “DHA-rich fish oil improves complex reaction time in female elite soccer players.” J Sports Sci Med 10:301–305 (2011)

Hardie DG. “AMP-activated protein kinase: A key system mediating metabolic responses to exercise.” Med Sci Sports Exerc 36: 28–34 (2004)

Hardie DG, Ross FA, and Hawley SA. “AMP-activate protein kinase: A target for drugs both ancient and modern.” Chem Bio 19: 1222–1236 (2012)

Hardie DG. “Keeping the home fires burning: AMP-activated protein kinase.” J Royal Society Interface 15: 20170774 (2018)

Hezel MP and Weitzberg E. “The oral microbiome and nitric oxide homoeostasis.” Oral Dis 21: 7–16 (2015)

Hostetler HA, Petrescu AD, Kier AB, and Schroeder F. “Peroxisome proliferator- activated receptor alpha interacts with high affinity and is conformationally responsive to endogenous ligands.” J Biol Chem 280: 18667–18682 (2005)

Huffman DM, Altena TS, Mawhinney TP, and Thomas TR. “Effect of n-3 fatty acids on free tryptophan and exercise fatigue.” Eur J Appl Physiol 92: 584–591 (2004)

Hwang JT, Kwon DY, and Yoon SH. “AMP-activated protein kinase: A potential target for disease prevention by natural occurring polyphenols.” N Biotechnol 26: 17–22 (2009) 

Jessen N, Sundelin EI, and Møller AB. “AMP kinase in exercise adaptation of skeletal muscle.” Drug Discov Today 19: 999–1002 (2014)

Jouris KB, McDaniel JL, and Weiss EP. “The effect of omega-3 fatty acid supplementation on the inflammatory response to eccentric strength exercise.” J Sports Sci Med 10:432–438 (2011)

Kane MO, Sene M, Anselm E, Dal S, Schini-Kerth VB, and Augier C. “Role of AMP- activated protein kinase in NO- and EDHF-mediated endothelium-dependent relaxations to red wine polyphenols.” Indian J Physiol Pharmacol 59: 369–379 (2015)

Kawabata F, Neya M, Hamazaki K, Watanabe Y, Kobayashi S, and Tsuji T. “Supplementation with eicosapentaenoic acid-rich fish oil improves exercise economy and reduces perceived exertion during submaximal steady-state exercise in normal healthy untrained men.” Biosci Biotechnol Biochem 78: 2081–2028 (2014)

Know, L. Life: The epic story of our mitochondria. Friesen Press. Victoria, BC, Canada (2014)

Lane N. Power, Sex, and Suicide: Mitochondria and the meaning of life. Oxford University Press. Oxford, UK (2005)

Lantier L, Fentz J, Mounier R, Leclerc J, Treebak JT, Pehmøller C, Sanz N, Sakakibara I, Saint-Amand E, Rimbaud S, Maire P, Marette A, Ventura-Clapier R, Ferry A, Wojtaszewski JF, Foretz M, and Viollet B. “AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity.” FASEB J 28: 3211–3224 (2014)

Layman DK and Baum JI. “Dietary protein impact on glycemic control during weight loss.” J Nutr 134: 968S–973S (2004)

Layman DK, Anthony TG, Rasmussen BB, Adams SH, Lynch CJ, Brinkworth GD, and Davis TA. “Defining meal requirements for protein to optimize metabolic roles of amino acids.” Am J Clin Nutr 101: 1330S–1338S (2015)

Lewis EJ, Radonic PW, Wolever TM, and Wells GD. “21 days of mammalian omega-3 fatty acid supplementation improves aspects of neuromuscular function and performance in male athletes compared to olive oil placebo.” J Int Soc Sports Nutr 12: 28 (2015)

Lembke P, Capodice J, Hebert K, and Swenson T. “Influence of omega-3 index on performance and wellbeing in young adults after heavy eccentric exercise.” J Sports Sci Med 13: 151–156 (2014).

LeMond G and Hom M. The Science of Fitness. Academic Press. Waltham, MA (2015)

Maillet D and Weber JM. “Performance enhancing role of dietary fatty acids in a long-distance migrant shorebird.” J Exp Bio 209: 2686–2695 (2006)

Maillet D and Weber JM. “Relationship between n-3 PUFA content and energy metabolism in the flight muscles of a migrating shorebird.” J Exp Biol 210: 413–420 (2007)

Marcinko K and Steinberg GR. “The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise. Exp Physiol 99: 158–1585 (2014)

Marsh CE, Carter HH, Guelfi KJ, Smith KJ, Pike KE, Naylor LH, and Green DJ. “Brachial and cerebrovascular functions are enhanced in postmenopausal women after ingestion of chocolate with a high concentration of cocoa.” J Nutr 147:1686–1692 (2017)

Mickelborough TD. “Omega-3 polyunsaturated fatty acids in physical performance optimization.” Int J Sport Nutr Exec Metab 23: 83–96 (2013)

Mills JD, Bailes JE, Sedney CL, Hutchins H, and Sears B. “Omega-3 dietary supplementation reduces traumatic axonal injury in a rodent head injury model.” J Neurosurgery 114: 77–84 (2011)

Mounier R, Théret M, Lantier L, Foretz M, and Viollet B. “Expanding roles for AMPK in skeletal muscle plasticity.” Trends Endocrinol Metab 26: 275–286 (2015)

Niederberger E, King TS, Russe OQ, and Geisslinger G. “Activation of AMPK and its impact on exercise capacity.” Sports Med 45: 1497–1509 (2015)

Norton LE and Layman DK. “Leucine regulates translation initiation of protein synthesis in skeletal muscle after exercise.” J Nutr 136: 533S–537S (2006)

O’Brien RJ and Wong PC. “Amyloid precursor protein processing and Alzheimer’s disease.” Annu Rev Neurosci 34: 185–204 (2011)

Phillips SM. “A brief review of critical processes in exercise-induced muscular hypertrophy.” Sports Med 44 (Suppl 1): S71–77 (2014)

Phillips T, Childs AC, Dreon DM, Phinney S, and Leeuwenburgh C. “A dietary supplement attenuates IL-6 and CRP after eccentric exercise in untrained males.” Med Sci Sports Exerc 35: 2032–2037 (2003)

Pons V, Riera J, Capó X, Martorell M, Sureda A, Tur JA, Drobnic F, and Pons A. “Calorie restriction regime enhances physical performance of trained athletes.” J Int Soc Sports Nutr. 2018 Mar 9;15:12.

Poprzecki S, Zajac A, Chalimoniuk M, Waskiewicz Z, and Langfort J. “Modification of blood antioxidant status and lipid profile in response to high-intensity endurance exercise after low doses of omega-3 polyunsaturated fatty acid supplementation in healthy volunteers.” Int J Food Sci Nutr 60: 67–79 (2009)

Reznick RM and Shulman GI. “The role of AMP-activated protein kinase in mitochondrial biogenesis.” J Physiol 574(Pt 1): 33–39 (2006)

Richter EA and Ruderman NB. “AMPK and the biochemistry of exercise: Implications for human health and disease.” Biochem J 418: 261–275 (2009)

Rodacki CL, Rodacki AL, Pereira G, Naliwaiko K, Coelho I, Pequito D, and Fernandes LC. “Fish oil supplementation enhances the effects of strength training in elderly women.” Am J Clin Nutr 95: 428–436 (2012)

Rodriguez-Mateos A, Hezel M, Aydin H, Kelm M, Lundberg JO, Weitzberg E, Spencer JP, and Heiss C. “Interactions between cocoa flavanols and inorganic nitrate: Additive effects on endothelial function at achievable dietary amounts.” Free Radic Biol Med 80: 121–128 (2015) 

Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, and Ido Y. “AMPK and SIRT1: A long-standing partnership?” Am J Physiol Endocrinol Metabl 298: E751–E760 (2010)

Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, and Frisén J. “Retrospective birth dating of cells in humans.” Cell 122: 133–143 (2005)

Su W and Jones PJ. “Dietary fatty acid composition influences energy accretion in rats.” J Nutr 123: 2109–2114 (1993)

Tartibian B, Maleki BH, and Abbasi A. “The effects of ingestion of omega-3 fatty acids on perceived pain and external symptoms of delayed onset muscle soreness in untrained men.” Clin J Sport Med 19: 115–119 (2009)

Tartibian B, Maleki BH, and Abbasi A. “The effects of omega-3 supplementation on pulmonary function of young wrestlers during intensive training.” J Sci Med Sport 13: 281–286 (2010)

Tartibian B, Maleki BH, and Abbasi A. “Omega-3 fatty acids supplementation attenuates inflammatory markers after eccentric exercise in untrained men.” Clin J Sport Med 21: 131–137 (2011)

Tinsley GM, Gann JJ, Huber SR, Andre TL, La Bounty PM, Bowden RG, Gordon PM, and Grandjean PW. “Effects of fish oil supplementation on post resistance exercise muscle soreness.” J Diet Suppl 21: 1–12 (2016)

van Loon LJ and Goodpaster BH. “Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state.” Pflugers Arch 451:606–616 (2006)

Viru A. Hormones in Muscular Activity. CRC Press. Boca Raton, FL (1985)

von Schacky C, Kemper M, Haslbauer R, and Halle M. “Low omega-3 index in 106 German elite winter endurance athletes: A pilot study.” Int J Sport Nutr Exerc Metab 24: 559–564 (2014)

Weber JM “Metabolic fuels: Regulating fluxes to select mix.” J Exp Biol 214: 286– 294 (2011)

White AM, Johnston CS, Swan PD, Tjonn SL, and Sears B. “Blood ketones are directly related to fatigue and perceived effort during exercise in overweight adults adhering to low-carbohydrate diets for weight loss: A Pilot study.” J Am Diet Assoc 107: 1792–1796 (2007)

Whitten P. “Stanford’s secret weapon.” Swimming World. March/April (1993)

Williams M, Raven PB, Fogt DL, and Ivy JL. “Effects of recovery beverages on glycogen restoration and endurance exercise performance.” J Strength Cond Res. 2003 Feb;17(1):12–9.

Wilson PB and Madrigal LA. “Associations between whole blood and dietary omega-3 polyunsaturated fatty acid levels in collegiate athletes.” Int J Sport Nutr Exerc Metab 26: 497–505 (2016)

Winder WW, Taylor EB, and Thomson DM. “Role of AMP-activated protein kinase in the molecular adaptation to endurance exercise.” Med Sci Sports Exerc 38: 1945–1949 (2006) 

Wroble K, Trott MN, Schweitzer GG, Rahman RS, Kelly PV, and Weiss EP. “Low- carbohydrate, ketogenic diet impairs anaerobic exercise performance in exercise-trained women and men: a randomized-sequence crossover trial.” J Sports Med Phys Fitness 59: 600–607 (2019)

Xu ZR, Tan ZJ, Zhang Q, Gui QF, and Yang YM. “The effectiveness of leucine on muscle protein synthesis, lean body mass and leg lean mass accretion in older people: Systematic review and meta-analysis.” Br J Nutr 113: 25–34 (2015)

κebrowska A, Mizia-Stec K, Mizia M, Gκsior Z, and Poprzκcki S. “Omega-3 fatty acids supplementation improves endothelial function and maximal oxygen uptake in endurance-trained athletes.” Eur J Sport Sci 15: 305–314 (2015)

Zhao L, Zou T, Gomez NA, Wang B, Zhu MJ, and Du M. “Raspberry alleviates obesity- induced inflammation and insulin resistance in skeletal muscle through activation of AMP-activated protein kinase (AMPK)” Nutr Diabetes 8: 39 (2018)

Zoladz JA, Koziel A, Woyda-Ploszczyca A, Celichowski J, and Jarmuszkiewicz “Endurance training increases the efficiency of rat skeletal muscle mitochondria.” Pflugers Arch 468: 1709–1724 (2016)

CHAPTER 18: WHY DO WE GET FAT?

Arentson-Lantz E, Clairmont S, Paddon-Jones D, Tremblay A, and Elango R. “Protein: A nutrient in focus.” Appl Physiol Nutr Metab 40: 755–761 (2015)

Avena NM, Bocarsly ME, and Hoebel BG. “Animal models of sugar and fat bingeing: Relationship to food addiction and increased body weight.” Methods Mol Biol 829: 351–65 (2012)

Cai D. “Neuroinflammation and neurodegeneration in overnutrition-induced diseases.” Trends Endocrinol Metab 24: 40–47 (2013)

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, and Burcelin R. “Metabolic endotoxemia initiates obesity and insulin resistance.” Diabetes 56: 1761–1772 (2007)

Crewe C, An YA, and Scherer PE. “The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis, and impaired angiogenesis.” J Clin Invest 127: 74–82 (2017)

Fildes A, Charlton J, Rudisill C, Littlejohns P, Prevost AT, and Gulliford MC. “Probability of an obese person attaining normal body weight: Cohort study using electronic health records”. Am J Public Health 105: e54–59 (2015)

Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, Brychta R, Chen KY, Skarulis MC, Walter M, Walter PJ, and Hall KD. “Persistent metabolic adaptation 6 years after “The Biggest Loser” competition.” Obesity 24: 1612–1619 (2016)

Gray B, Steyn F, Davies PS, and Vitetta L. “Omega-3 fatty acids: A review of the effects on adiponectin and leptin and potential implications for obesity management.” Eur J Clin Nutr 67: 1234–1242 (2013) 

Gregor MF and Hotamisligil GS. “Inflammatory mechanisms in obesity.” Annu Rev Immunol 29: 415–445 (2011)

Guyenet SJ. The Hungry Brain. Flatiron Books. New York, NY (2017) Haghiac M, Yang XH, Presley L, Smith S, Dettelback S, Minium J, Belury MA, Catalano PM, and Hauguel-de Mouzon S. “Dietary omega-3 fatty acid supplementation reduces inflammation in obese pregnant women: A randomized double-blind controlled clinical trial.” PLoS One 10: e0137309 (2015)

Hall KD, Chen KY, Guo J, Lam YY, Leibel RL, Mayer LE, Reitman ML, Rosenbaum M, Smith SR, Walsh BT, and Ravussin E. “Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men.” Am J Clin Nutr 104: 324–333 (2016)

Hellström PM. “Satiety signals and obesity.” Curr Opin Gastroenterol 29: 222–227 (2013)

Hernandez TL, Kittelson JM, Law CK, Ketch LL, Stob NR, Lindstrom RC, Scherzinger A, Stamm ER, and Eckel RH. “Fat redistribution following suction lipectomy: Defense of body fat and patterns of restoration.” Obesity 19: 1388– 1395 (2011)

Johnson C, Day CS, and Swan PD. “Postprandial thermogenesis is increased 100% on a high-protein, low-fat diet versus a high-carbohydrate, low-fat diet in healthy, young women.” J Amer Coll Nutr 21: 55–61 (2002)

Kaliannan K, Wang B, Li XY, Kim KJ, and Kang JX. “A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia.” Sci Rep 5:11276 (2015)

Keith SW, Redden DT, Katzmarzyk PT, Boggiano MM, Hanlon EC, Benca RM, Ruden D, Pietrobelli A, Barger JL, Fontaine KR, Wang C, Aronne LJ, Wright SM, Baskin M, Dhurandhar NV, Lijoi MC, Grilo CM, DeLuca M, Westfall AO, and Allison DB. “Putative contributors to the secular increase in obesity: Exploring the roads less traveled.” Int J Obes 30: 1585–1594 (2006)

Kim J, Li Y, and Watkins BA. “Fat to treat fat: Emerging relationship between dietary PUFA, endocannabinoids, and obesity.” Prostaglandins Other Lipid Mediat 104-105: 32–41 (2013)

Kraemer FB, Takeda D, Natu V, and Sztalryd C. “Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways.” Metabolism 47: 555–559 (1998)

le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos A, Laurenius A, Lönroth H, Fändriks L, Ghatei MA, Bloom SR, and Olbers T. “Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass.” Ann Surg 246: 780–785 (2007)

Li C, Ford ES, Zhao G, Balluz LS, and Giles WH. “Estimates of body composition with dual-energy X-ray absorptiometry in adults.” Am J Clin Nutr 90: 1457– 1465 (2009)

Lustig RH. “Childhood obesity: Behavioral aberration or biochemical drive? Reinterpreting the first law of thermodynamics.” Nat Clin Pract Endocrinol Metab 2: 447–458 (2006)

Maric T, Woodside B, and Luheshi GN. “The effects of dietary saturated fat on basal hypothalamic neuroinflammation in rats.” Brain Behav Immun 36: 35–45 (2014)

McGuire MT, Wing RR, Klem ML, Seagle HM, and Hill JO. “Long-term maintenance of weight loss: Do people who lose weight through various weight loss methods use different behaviors to maintain their weight?” Int J Obes Relat Metab Disord 22: 572–577 (1998)

Morris MJ, Beilharz JE, Maniam J, Reichelt AC, and Westbrook RF. “Why is obesity such a problem in the 21st century? The intersection of palatable food, cues and reward pathways, stress, and cognition.” Neurosci Biobehav Rev 58: 36–45 (2015)

Muhammad HFL, Vink RG, Roumans NJT, Arkenbosch LAJ, Mariman EC, and van Baak MA. “Dietary intake after weight loss and the risk of weight regain: Macronutrient composition and inflammatory properties of the diet.” Nutrients 9: 11 (2017)

Murray S, Tulloch A, Gold MS, and Avena NM. “Hormonal and neural mechanisms of food reward, eating behaviour and obesity.” Nat Rev Endocrinol 10: 540–552 (2014)

Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR, and Frost G. “The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents.” Int J Obes 39: 424–429 (2015)

Raynor HA, Jeffery RW, Phelan S, Hill JO, and Wing RR. “Amount of food group variety consumed in the diet and long-term weight loss maintenance.” Obes Res 13: 883–890 (2005)

Ruderman NB, Carling D, Prentki M, and Cacicedo JM. “AMPK, insulin resistance, and the metabolic syndrome.” J Clin Invest 123: 2764–2772 (2013)

Sáinz N, González-Navarro CJ, Martínez JA, and Moreno-Aliaga MJ. “Leptin signaling as a therapeutic target of obesity.” Expert Opin Ther Targets 19: 893– 909 (2015)

Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)

Sears B. The Mediterranean Zone. Ballantine Books. New York, NY (2014)

Sears B and Perry M. “The role of fatty acids in insulin resistance.” Lipids Health Disease 14: 121 (2015)

Shick SM, Wing RR, Klem ML, McGuire MT, Hill JO, and Seagle H. “Persons successful at long-term weight loss and maintenance continue to consume a low-energy, low-fat diet.” J Am Diet Assoc 98: 408–413 (1998)

Sun K, Kusminski CM, and Scherer PE. “Adipose tissue remodeling and obesity.” J Clin Invest 121: 2094–2101 (2011) van der Klaauw AA, Keogh JM, Henning E, Trowse VM, Dhillo WS, Ghatei MA, and Farooqi IS. “High protein intake stimulates postprandial GLP-1 and PYY release.” Obesity 21: 1602–1607 (2013) van devijvere S, Chow CC, Hall KD, Umali E, and Swinburn BA. “Increased food energy supply as a major driver of the obesity epidemic: A global analysis.” Bull World Heath Organ 93: 446–456 (2015)

Vink RG, Roumans NJ, Arkenbosch LA, Mariman EC, and van Baak MA. “The effect of rate of weight loss on long-term weight regain in adults with overweight and obesity.” Obesity 24: 321–327 (2016)

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, and Ferrante AW. “Obesity is associated with macrophage accumulation in adipose tissue.” J Clin Invest 112: 1796–1808 (2003)

Zhou QY and Palmiter RD. “Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic.” Cell 83: 1197–1209 (1995)

CHAPTER 19: WHY DO WE GET SICK?

Ahmed S, Mahmood Z, and Zahid S. “Linking insulin with Alzheimer’s disease: Emergence as type III diabetes.” Neurol Sci 36: 1763–1769 (2015)

Amminger GP, Schäfer MR, Schlögelhofer M, Klier CM, and McGorry PD. “Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study.” Nat Commun 6: 7934 (2015)

Baidal DA, Ricordi C, Garcia-Contreras M, Sonnino A, and Fabbri A. “Combination high-dose omega-3 fatty acids and high-dose cholecalciferol in new onset type 1 diabetes: A potential role in preservation of beta-cell mass.” Eur Rev Med Pharmacol Sci 20: 3313–3318 (2016)

Bellamkonda K, Chandrashekar NK, Osman J, Selvanesan BC, Savari S, and Sjölander A. “The eicosanoids leukotriene D4 and prostaglandin E2 promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model.” BMC Cancer 16: 425 (2016)

Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, Allen NB, Stuart AL, Hayley AC, Byrne ML, and Maes M. “So depression is an inflammatory disease, but where does the inflammation come from?” BMC Med 11: 200 (2013)

Bienenstock J, Kunze W, and Forsythe P. “Microbiota and the gut-brain axis.” Nutr Rev 73 (Suppl 1): 28–31 (2015)

Bos DJ, Oranje B, Veerhoek ES, Van Diepen RM, Weusten JM, Demmelmair H, Koletzko B, de Sain-van der Velden MG, Eilander A, Hoeksma M, and Durston S. “Reduced symptoms of inattention after dietary omega-3 fatty acid supplementation in boys with and without attention deficit/hyperactivity disorder.” Neuropsychopharmacology 40: 2298–2306 (2015)

Burrell RA, McGranahan N, Bartek J, and Swanton C. “The causes and consequences of genetic heterogeneity in cancer evolution.” Nature 501: 338– 345 (2013) 

Buydens-Branchey L and Branchey M. “n-3 polyunsaturated fatty acids decrease anxiety feelings in a population of substance abusers.” J Clin Psychopharmacol 26: 661–665 (2006)

Buydens-Branchey L, Branchey M, and Hibbeln JR. “Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers.” Prog Neuropsychopharmacol Biol Psychiatry 32: 568–575 (2008)

Cadario F, Savastio S, Rizzo AM, Carrera D, Bona G, and Ricordi C. “Can Type 1 diabetes progression be halted? Possible role of high dose vitamin D and omega 3 fatty acids.” Eur Rev Med Pharmacol Sci 21: 1604–1609 (2017)

Chanock SJ. “The paradox of mutations and cancer.” Science 362: 893–894 (2018)

Chatterjee S, Peters SA, Woodward M, Mejia Arango S, Batty GD, Beckett N, Beiser A, Borenstein AR, Crane PK, Haan M, Hassing LB, Hayden KM, Kiyohara Y, Larson EB, Li CY, Ninomiya T, Ohara T, Peters R, Russ TC, Seshadri S, Strand BH, Walker R, Xu W, and Huxley RR. “Type 2 diabetes as a risk factor for dementia in women compared with men.” Diabetes Care 39: 300–307 (2016)

Catry E, Bindels LB, Tailleux A, Lestavel S, Neyrinck AM, Goossens JF, Lobysheva I, Plovier H, Essaghir A, Demoulin JB, Bouzin C, Pachikian BD, Cani PD, Staels B, Dessy C, and Delzenne NM. “Targeting the gut microbiota with insulin-type fructans: Preclinical demonstration of a novel approach in the management of endothelial dysfunction.” Gut 67: 271–283 (2018)

Centers for Disease Control. “More than 100 million Americans have diabetes or prediabetes.” Press Release July 18, 2017

Chiarini F, Evangelisti C, McCubrey JA, and Martelli AM. “Current treatment strategies for inhibiting mTOR in cancer.” Trends Pharmacol Sci 36: 124–135 (2015)

Conquer JA, Tierney MC, Zecevic J, Bettger WJ, and Fisher RH. “Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment.” Lipids 35: 1305–1312 (2000)

Crewe C, An YA, and Scherer PE. “The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis, and impaired angiogenesis.” J Clin Invest 127: 74–82 (2017)

Das UN. “Is multiple sclerosis a proresolution deficiency disorder?” Nutrition 28: 951–958 (2012)

DiDonato JA, Mercurio F, and Karin M. “NF-ϰB and the link between inflammation and cancer.” Immunol Rev 246:3 79–400 (2012)

Dinan TG and Cryan JF. “The microbiome-gut-brain axis in health and disease.” Gastroenterol Clin North Am 46: 77–89 (2017)

Eming SA, Wynn TA, and Martin P. “Inflammation and metabolism in tissue repair and regeneration.” Science 356: 1026–1030 (2017)

Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaeffer EJ, Wolff SM, and Dinarello CA. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” N Engl J Med 320: 265–271 (1989)

Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, and Lodi L. “Cognitive and physiological effects of omega-3 polyunsaturated fatty acid supplementation in healthy subjects.” Eur J Clin Invest 35: 691–699 (2005)

Frye RE, Rose S, Chacko J, Wynne R, Bennuri SC, Slattery JC, Tippett M, Delhey L, Melnyk S, Kahler SG, and MacFabe DF. “Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines.” Transl Psychiatry 6: e927 (2016)

Geovanini GR and Libby P. “Atherosclerosis and inflammation: Overview and updates.” Clin Sci 132: 1243–1252 (2018)

Germano M, Meleleo D, Montorfano G, Adorni L, Negroni M, Berra B, and Rizzo AM. “Plasma, red blood cells phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD).” Nutr Neurosci 10: 1–9 (2007)

Gustafsson PA, Birberg-Thornberg U, Duchen K, Landgren M, Malmberg K, Pelling H, Strandvik B, and Karlsson T. “EPA supplementation improves teacher-rated behaviour and oppositional symptoms in children with ADHD.” Acta Paediatr 99: 1540–1549 (2010)

Han QQ and Yu J. “Inflammation: A mechanism of depression?” Neurosci Bull 30:515–523 (2014)

Hardie DG. “AMPK: A target for drugs and natural products with effects on both diabetes and cancer.” Diabetes 62: 2164–2172 (2013)

Heydari B, Abdullah S, Pottala JV, Shah R, Abbasi S, Mandry D, Francis SA, Lumish H, Ghoshhajra BB, Hoffmann U, Appelbaum E, Feng JH, Blankstein R, Steigner M, McConnell JP, Harris W, Antman EM, Jerosch-Herold M, and Kwong RY. “Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction: The OMEGA-REMODEL randomized clinical trial.” Circulation 134: 378–391 (2016)

Huang CC, Chung CM, Leu HB, Lin LY, Chiu CC, Hsu CY, Chiang CH, Huang PH, Chen TJ, Lin SJ, Chen JW, and Chan WL. “Diabetes mellitus and the risk of Alzheimer’s disease: A nationwide population-based study.” PLoS One 9: e87095 (2014)

Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, and Matsuzawa Y. “Relationships between plasma fatty acid composition and coronary artery disease.” J Atheroscler Thromb 18: 99–107 (2011)

Jelinek GA, Hadgkiss EJ, Weiland TJ, Pereira NG, Marck CH, and van der Meer DM. “Association of fish consumption and n-3 supplementation with quality of life, disability and disease activity in an international cohort of people with multiple sclerosis.” Int J Neurosci 123: 792–800 (2013)

Kelly CT, Mansoor J, Dohm GL, Chapman WH, Pender JR, and Pories WJ. “Hyperinsulinemic syndrome: The metabolic syndrome is broader than you think.” Surgery 156: 405–411 (2014)

Khan A and Brown WA. “Antidepressants versus placebo in major depression: Overview.” World Psychiatry 14: 294–300 (2015)

Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, and Glaser R. “Omega-3 supplementation lowers inflammation and anxiety in medical students: Randomized controlled trial.” Brain Behav Immun 25: 1725–1734 (2011)

Kiecolt-Glaser JK, Derry HM, and Fagundes CP. “Inflammation: Depression fans the flames and feasts on the heat.” Am J Psychiatry 172: 1075–1091 (2015)

Klein CP, Sperotto ND, Maciel IS, Leite CE, Souza AH, and Campos MM. “Effects of D-series resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice.” Neuropharmacology 86: 57–66 (2014)

Kromann N and Green A. “Epidemiological studies in the Upernavik district, Greenland: Incidence of some chronic diseases 1950–1974.” Acta Med Scand 208: 401–406 (1980)

Laakso M. “Cardiovascular disease in type 2 diabetes from population to man to mechanisms.” Diabetes Care 33: 442–449 (2010)

La Chance L, McKenzie K, Taylor VH, and Vigod SN. “Omega-6 to omega-3 fatty acid ratio in patients with ADHD: A meta-analysis.” J Can Acad Adoles Psychiarty 25: 87–96 (2016)

Lazic M, Inzaugarat ME, Povero D, Zhao IC, Chen M, Nalbandian M, Miller YI, Cherñavsky AC, Feldstein AE, and Sears DD. “Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis.” PLoS One 9: e107658 (2014)

Lesperance F, Frasure-Smith N, St-Andre E, Turecki G, Lesperance P, and Wisniewski SR. “The efficacy of omega-3 supplementation for major depression: Randomized controlled trial.” J Clin Psychiatry 72: 1054–1062 (2011)

Li YC, Chen Y, and Du J. “Critical roles of intestinal epithelial vitamin D receptor signaling in controlling gut mucosal inflammation.” J Steroid Biochem Mol Biol 148: 179–183 (2015)

Li W, Saud SM, Young MR, Chen G, and Hua B. “Targeting AMPK for cancer prevention and treatment.” Oncotarget 6: 7365–7378 (2015)

Libby P, Ridker PM, and Maseri A. “Inflammation and atherosclerosis.” Circulation 105: 1135–1143 (2002)

Libby P. “Inflammation in atherosclerosis.” Arterio Thromb Vasc Biol 32: 2045– 2051 (2012) 

Libby P, Tabas I, Fredman G, and Fisher EA. “Inflammation and its resolution as determinants of acute coronary syndromes.” Circ Res 114: 1867–1879 (2014)

Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, and Taylor R. “Reversal of type 2 diabetes: Normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.” Diabetologia 54: 2506–2514 (2011)

Lotrich, FE, Sears, B, and McNamara RK. “Elevated ratio of arachidonic acid to long-chain omega-3 fatty acids predicts depression development following interferon-alpha treatment: Relationship with interleukin-6.” Brain, Behavior, and Immunity 31: 48–53 (2013)

Lotrich FE, Sears B, and McNamara R.K. “Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids.” J Psychosomatic Res 75: 475–483 (2013)

Ma K, Nunemaker CS, Wu R, Chakrabarti SK, Taylor-Fishwick DA, and Nadler JL. “12-lipoxygenase products reduce insulin secretion and beta-cell viability in human islets.” J Clin Endocrinol Metab 95: 887–893 (2010)

MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, Boon F, Taylor AR, Kavaliers M, and Ossenkopp KP. “Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders.” Behav Brain Res 176: 149–169 (2007)

Martincornea I, Folwer JC, Wabik A. Lawson ARJ, Abascal F, Hall MWJ, Cagan A, Murai K, Mahbubani K, Stratton MR, Fitzgerald RC, Handford PA, Campbell PJ, Saeb-Parsy K, and Jones PH. “Somatic mutant clones colonize the human esophagus with age.” Science 362: 911–917 (2018)

Martinez KE, Tucker LA, Bailey BW, and LeCheminant JD. “Expanded normal weight obesity and insulin resistance in US adults of the National Health and Nutrition Examination Survey.” J Diabetes Res 2017: 9502643 (2017)

Markovic TP, Jenkins AB, Campbell LV, Furler SM, Kraegen EW, and Chisholm DJ. “The determinants of glycemic responses to diet restriction and weight loss in obesity and NIDDM.” Diabetes Care 21: 687–694 (1998)

Martins JG. “EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: Evidence from a meta-analysis of randomized controlled trials.” J Am Coll Nutr 28:525–542 (2009)

Mazza M, Marano G, Traversi G, Di Nicola M, Catalano V, and Janiri L. “The complex interplay of depression, inflammation and omega-3: State of the art and progresses in research.” Clin Ter 166: e242–247 (2015)

McNamara RK, Perry M, and Sears, B. “Dissociation of C-reactive protein levels from long-chain omega-3 fatty acid status and anti-depressant response in adolescents with major depressive disorder: An open-label dose-ranging trial.” J Nutr Therapeutics 2:235–243 (2013) 

Miller AH and Raison CL. “The role of inflammation in depression: From evolutionary imperative to modern treatment target.” Nat Rev Immunology 16: 22–34 (2016)

Miller PE, Van Elswyk M, and Alexander DD. “Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: A meta- analysis of randomized controlled trials.” Am J Hypertens 27: 885–96 (2014)

Mills JD, Bailes JE, Sedney CL, Hutchins H, and Sears B. “Omega-3 dietary supplementation reduces traumatic axonal injury in a rodent head injury model.” J Neurosurgery 114: 77–84 (2011)

Milte CM, Parletta N, Buckley JD, Coates AM, Young RM, and Howe PR. “Increased erythrocyte eicosapentaenoic acid and docosahexaenoic acid are associated with improved attention and behavior in children with ADHD in a randomized controlled three-way crossover trial.” J Atten Disord 19: 954–964 (2015)

Möhler H. “The GABA system in anxiety and depression and its therapeutic potential.” Neuropharmacology 62: 42–53 (2016)

Mozaffari-Khosravi H, Yassini-Ardakani M, Karamati M, and Shariati-Bafghi SE. “Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: A randomized, double-blind, placebo-controlled trial.” Eur Neuropsychopharmacol 23: 636–644 (2013)

Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, and Gordon E. “Metabolic features of chronic fatigue syndrome.” Proc Natl Acad Sci U S A 113: E5472–5480 (2016)

Nemets H, Nemets B, Apter A, Bracha Z, and Belmaker RH. “Omega-3 treatment of childhood depression: A controlled, double-blind pilot study.” Am J Psychiatry 163: 1098–1100 (2006)

Nordvik I, Myhr KM, Nyland H, and Bjerve KS. “Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients.” Acta Neurol Scand 102: 143–149 (2000)

Oshima H and Oshima M. “The role of PGE2-associated inflammatory responses in gastric cancer development.” Semin Immunopathol 35: 139–150 (2013)

Rehman G, Shehzad A, Khan AL, and Hamayun M. “Role of AMP-activated protein kinase in cancer therapy.” Arch Pharm 347: 457–468 (2014)

Ruderman NB, Carling D, Prentki M, and Cacicedo JM. “AMPK, insulin resistance, and the metabolic syndrome.” J Clin Invest 123: 2764–2772 (2013)

Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)

Sears B, Bailes J, and Asselin B. “Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury.” PharmaNutrition 1: 86–89 (2013)

Sekikawa A, Steingrimsdottir L, Ueshima H, Shin C, Curb JD, Evans RW, Hauksdottir AM, Kadota A, Choo J, Masaki K, Thorsson B, Launer LJ, Garcia  ME, Maegawa H, Willcox BJ, Eiriksdottir G, Fujiyoshi A, Miura K, Harris TB, Kuller LH, and Gudnason V. “Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanese, Koreans, and Americans—a descriptive epidemiologic study.” Prostaglandins Leukot Essent Fatty Acids 87: 11–16 (2012)

Seyfried TN. Cancer as a Metabolic Disease. Wiley and Sons. Hoboken, NJ (2012)

Seyfried TN, Flores RE, Poff AM, and D’Agostino DP. “Cancer as a metabolic disease: Implications for novel therapeutics.” Carcinogenesis 35: 515–527 (2014)

Shattuck EC and Muehlenbein MP. “Towards an integrative picture of human sickness behavior.” Brain Behav Immun 57: 255–262 (2016)

Solano C, Echeverz M, and Lasa I. “Biofilm dispersion and quorum sensing.” Curr Opin Microbiol 18: 96–104 (2014)

Sorgi PJ, Hallowell EM, Hutchins HL, and Sears B. “Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder.” Nutr J 13: 16 (2007)

Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, and Frisén J. “Retrospective birth dating of cells in humans.” Cell 122: 133–143 (2005)

Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, and Frisén J. “Dynamics of hippocampal neurogenesis in adult humans.” Cell 153: 1219–1227 (2013)

Stene LC and Joner G. “Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: A large, population-based, case-control study.” Am J Clin Nutr 78: 1128–1134 (2003)

Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, and Marangell LB. “Omega 3 fatty acids in bipolar disorder: A preliminary double- blind, placebo-controlled trial.” Arch Gen Psychiatry 56: 407–412 (1999)

Su KP, Huang SY, Chiu CC, and Shen WW. “Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial.” Eur Neuropsychopharmacol 13: 267–271 (2003)

Su D, Nie Y, Zhu A, Chen Z, Wu P, Zhang L, Luo M, Sun Q, Cai L, Lai Y, Xiao Z, Duan Z, Zheng S, Wu G, Hu R, Tsukamoto H, Lugea A, Liu Z, Pandol SJ, and Han YP. “Vitamin D signaling through induction of Paneth cell defensins maintains gut microbiota and improves metabolic disorders and hepatic steatosis in animal models.” Front Physiol 7: 498 (2016)

Sulciner ML, Serhan CN, Gilligan MM, Mudge DK, Chang J, Gartung A, Lehner KA, Bielenberg DR, Schmidt B, Dalli J, Greene ER, Gus-Brautbar Y, Piwowarski J, Mammoto T, Zurakowski D, Perretti M, Sukhatme VP, Kaipainen A, Kieran MW, Huang S, and Panigrahy D. “Resolvins suppress tumor growth and enhance cancer therapy.” J Exp Med 215: 115–140 (2018)

Taylor-Fishwick DA, Weaver J, Glenn L, Kuhn N, Rai G, Jadhav A, Simeonov A, Dudda A, Schmoll D, Holman TR, Maloney DJ, and Nadler JL. “Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction.” Diabetologia 58: 549–57 (2015)

Tessaro FH, Ayala TS, and Martins JO. “Lipid mediators are critical in resolving inflammation: A review of the emerging roles of eicosanoids in diabetes mellitus.” Biomed Res Int 2015: 568408 (2015)

Wang X, Zhu M, Hjorth E, Cortés-Toro V, Eyjolfsdottir H, Graff C, Nennesmo I, Palmblad J, Eriksdotter M, Sambamurti K, Fitzgerald JM, Serhan CN, Granholm AC, and Schultzberg M. “Resolution of inflammation is altered in Alzheimer’s disease.” Alzheimers Dement 11: 40–50 (2015)

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, and Ferrante AW. “Obesity is associated with macrophage accumulation in adipose tissue.” J Clin Invest 112: 1796–1808 (2003)

Wenzlau JM and Hutton JC. “Novel diabetes autoantibodies and prediction of type 1 diabetes.” Curr Diab Rep 13: 608–615 (2013)

Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, Sgonc R, and Wolfram D. “The immunology of fibrosis.” Annu Rev Immunol 31: 107–135 (2013)

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis.” Lancet 369: 1090–1098 (2007)

Wynn TA. “Cellular and molecular mechanisms of fibrosis.” J Pathol 214: 199–210 (2008)

CHAPTER 20: WHY DO WE AGE?

Allan CA, Strauss BJ, Burger HG, Forbes EA, and McLachlan RI. “Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men.” J Clin Endocrinol Metab 93: 139–46 (2008)

Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, Suematsu M, Hirose N, and von Zglinicki T. “Inflammation, but not telomere length, predicts successful ageing at extreme old age: A longitudinal study of semi- supercentenarians.” EBioMedicine 2: 1549–1558 (2015)

Barzilai N, Cuervo AM, and Austad S. “Aging as a biological target for prevention and therapy.” JAMA 320: 1321–1322 (2018)

Brattbakk HR, Arbo I, Aagaard S, Lindseth I, de Soysa AK, Langaas M, Kulseng B, Lindberg F, and Johansen B. “Balanced caloric macronutrient composition downregulates immunological gene expression in human blood cells-adipose tissue diverges.” OMICS 17: 41–52 (2013)

Calder PC, Bosco N, Bourdet-Sicard R, Capuron L, Delzenne N, Doré J, Franceschi C, Lehtinen MJ, Recker T, Salvioli S, and Visioli F. “Health relevance of the modification of low-grade inflammation in ageing (inflammageing) and the role of nutrition.” Ageing Res Rev 40: 95–119 (2017)

Cardel M, Jensen SM, Pottegård A, Jørgensen TL, and Hallas J. “Long-term use of metformin and colorectal cancer risk in type II diabetics: A population-based case-control study.” Cancer Med 3: 1458–1466 (2014)

Das SK, Gilhooly CH, Golden JK, Pittas AG, Fuss PJ, Cheatham RA, Tyler S, Tsay M, McCrory MA, Lichtenstein AH, Dallal GE, Dutta C, Bhapkar MV, Delany JP, Saltzman E, and Roberts SB. “Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: A 1-y randomized controlled trial.” Am J Clin Nutr. 85: 1023–1030 (2007)

Das SK, Roberts SB, Bhapkar MV, Villareal DT, Fontana L, Martin CK, Racette SB, Fuss PJ, Kraus WE, Wong WW, Saltzman E, Pieper CF, Fielding RA, Schwartz AV, Ravussin E, and Redman LM. “Body-composition changes in the comprehensive assessment of long-term effects of reducing intake of energy (CALERIE)-2 study: A 2-y randomized controlled trial of calorie restriction in nonobese humans.” Am J Clin Nutr 105: 913–927 (2017)

Fishman JR, Flatt MA, and Settersten RA. “Bioidentical hormones, menopausal women, and the lure of the ‘natural’ in U.S. anti-aging medicine.” Soc Sci Med 132: 79–87 (2015)

Fontana L, Klein S, and Holloszy JO. “Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production.” Age 32: 97–108 (2010)

Fontana L, Kennedy BK, Longo VD, Seals D, and Melov S. “Medical research: Treat ageing.” Nature 511: 405–407 (2014)

Fontana L, Villareal DT, Das SK, Smith SR, Meydani SN, Pittas AG, Klein S, Bhapkar M, Rochon J, Ravussin E, and Holloszy JO. “Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: A randomized clinical trial.” Aging Cell 15: 22–27 (2016)

Franceschi C and Campisi J. “Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.” J Gerontol A Biol Sci Med Sci 69 (Suppl 1): S4–9 (2014)

Giampieri F, Alvarez-Suarez JM, Cordero MD, Gasparrini M, Forbes-Hernandez TY, Afrin S, Santos-Buelga C, González-Paramás AM, Astolfi P, Rubini C, Zizzi A, Tulipani S, Quiles JL, Mezzetti B, and Battino M. “Strawberry consumption improves aging-associated impairments, mitochondrial biogenesis and functionality through the AMP-activated protein kinase signaling cascade.” Food Chem 234: 464–471 (2017)

Gottlieb RA and Gustafsson AB. “Mitochondrial turnover in the heart.” Biochim Biophys Acta 1813: 1295–1301 (2011)

Gottlieb RA and Stotland A. “MitoTimer: A novel protein for monitoring mitochondrial turnover in the heart.” J Mol Med 93: 271–278 (2015)

Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, and Ravussin E. “Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: A randomized controlled trial.” JAMA 295: 1539–1548 (2006)

Hung WW, Ross JS, Boockvar KS, and Siu AL. “Recent trends in chronic disease, impairment and disability among older adults in the United States.” BMC Geriatrics 11: 47 (2011)

Kaeberlein M, Rabinovitch PS, and Martin GM. “Healthy aging: The ultimate preventative medicine.” Science 350: 1191–1193 (2015)

Kain V, Ingle KA, Kachman M, Baum H, Shanmugam G, Rajasekaran NS, Young ME, and Halade GV. “Excess n-6 fatty acids influx in aging drives metabolic dysregulation, electrocardiographic alterations, and low-grade chronic inflammation.” Am J Physiol Heart Circ Physiol 314: H160–H169 (2018)

Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, and Blackburn E. “Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial.” Brain Behav Immun 28: 16–24 (2013)

Lewis KN, Wason E, Edrey YH, Kristan DM, Nevo E, and Buffenstein R. “Regulation of Nrf2 signaling and longevity in naturally long-lived rodents.” Proc Natl Acad Sci U S A. 112: 3722–3727 (2015)

Liang J and Shang Y. “Estrogen and cancer.” Annu Rev Physiol 75: 225–240 (2013)

Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, and Fontana L. “Interventions to slow aging in humans: Are we ready?” Aging Cell 14: 497–510 (2015)

Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, and Bjorntorp P. “The effects of testosterone treatment on body composition and metabolism in middle-aged obese men.” Int J Obes Relat Metab Disord 16: 991–997 (1992)

Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye- Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, and de Cabo R. “Metformin improves healthspan and lifespan in mice.” Nat Commun 4: 2192 (2013)

McCay CM and Crowell MF. “Prolonging the life span.” Scientific Monthly 39: 405–414 (1934)

Mendelsohn AR and Larrick JW. “Inflammation, stem cells, and the aging hypothalamus.” Rejuvenation Res 20: 346–349 (2017) 

Meydani SN, Das SK, Pieper CF, Lewis MR, Klein S, Dixit VD, Gupta AK, Villareal DT, Bhapkar M, Huang M, Fuss PJ, Roberts SB, Holloszy JO, and Fontana “Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: A randomized controlled trial in non-obese humans.” Aging 8: 1416–1431 (2016)

Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, Brody J, Hayflick L, Butler RN, Allison DB, and Ludwig DS. “A potential decline in life expectancy in the United States in the 21st century.” N Engl J Med 352: 1138–1145 (2005)

Olshansky SJ. “From lifespan to healthspan.” JAMA 320: 1323–1324 (2018)

Owen MR, Doran E, and Halestrap AP. “Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.” Biochem J 348 (Pt 3): 607–614 (2000)

Pandey MK, Gupta SC, Nabavizadeh A, and Aggarwal BB. “Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment.” Semin Cancer Biol 46: 158–181 (2017)

Pittas AG, Das SK, Hajduk CL, Golden J, Saltzman E, Stark PC, Greenberg AS, and Roberts SB. “A low-glycemic load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE Trial.” Diabetes Care 28: 2939–2941 (2005)

Prattichizzo F, De Nigris V, Spiga R, Mancuso E, La Sala L, Antonicelli R, Testa R, Procopio AD, Olivieri F, and Ceriello A. “Inflammageing and metaflammation: The yin and yang of type 2 diabetes.” Ageing Res Rev 41: 1–17 (2018)

Rabassa M, Cherubini A, Zamora-Ros R, Urpi-Sarda M, Bandinelli S, Ferrucci L, and Andres-Lacueva C. “Low levels of a urinary biomarker of dietary polyphenol are associated with substantial cognitive decline over a 3-year period in older adults: The Invecchiare in Chianti study.” J Am Geriatr Soc 63: 938–946 (2015)

Rabassa M, Zamora-Ros R, Andres-Lacueva C, Urpi-Sarda M, Bandinelli S, Ferrucci L, and Cherubini A. “Association between both total baseline urinary and dietary polyphenols and substantial physical performance decline risk in older adults: A 9-year follow-up of the InCHIANTI study.” J Nutr Health Aging 20: 478–485 (2016)

Racette SB, Weiss EP, Villareal DT, Arif H, Steger-May K, Schechtman KB, Fontana L, Klein S, and Holloszy JO. “One year of caloric restriction in humans: Feasibility and effects on body composition and abdominal adipose tissue.” J Gerontol A Biol Sci Med Sci 61: 943–950 (2006)

Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, and Ross OA. “Age and age-related diseases: Role of inflammation triggers and cytokines.” Front Immunol 9: 586 (2018)

Reubinoff BE, Wurtman J, Rojansky N, Adler D, Stein P, Schenker JG, and Brzezinski A. “Effects of hormone replacement therapy on weight, body composition, fat distribution, and food intake in early postmenopausal women: A prospective study.” Fertil Steril 64: 963–968 (1995) 

Salminen A and Kaarniranta K. “AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.” Ageing Res Rev 11: 230–241 (2012)

Sears B. The Zone. Regan Books. New York, NY (1995)

Sears B. The Anti-Aging Zone. Regan Books. New York, NY (1999) Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)

Sears B. “Delaying adverse health consequences of aging: The role of omega-3 fatty acids on inflammation and resoleomics.” CellR4 4: e2111 (2016)

Spalding KL, Bhardwaj RD, Buchholz BA, Druid and H, and Frisén J. “Retrospective birth dating of cells in humans.” Cell 122: 133–143 (2005)

Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T, Concha H, Hassan M, Rydén M, Frisén J, and Arner P. “Dynamics of fat cell turnover in humans.” Nature 453: 783–787 (2008)

Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, and Frisén J. “Dynamics of hippocampal neurogenesis in adult humans.” 153: 1219–1227 (2013)

Stephenne X, Foretz M, Taleux N, van der Zon GC, Sokal E, Hue L, Viollet B, and Guigas B. “Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status.” Diabetologia 54: 3101–3110 (2011)

Sun N, Youle RJ, and Finkel T. “The mitochondrial basis of aging.” Mol Cell 61: 654–666 (2016)

Szklarczyk R, Nooteboom M, and Osiewacz HD. “Control of mitochondrial integrity in ageing and disease.” Philos Trans R Soc Lond B Biol Sci 369: 20130439 (2014)

Urpi-Sarda M, Andres-Lacueva C, Rabassa M, Ruggiero C, Zamora-Ros R, Bandinelli S, Ferrucci L, and Cherubini A. “The relationship between urinary total polyphenols and the frailty phenotype in a community-dwelling older population: The InCHIANTI study.” J Gerontol A Biol Sci Med Sci 70: 1141– 1147 (2015)

Ward BW, Schiller JS, and Goodman RA. “Multiple chronic conditions among US adults: A 2012 update.” Prev Chronic Dis 11: E62 (2014)

Welsh JA. Sharks Get Cancer, Mole Rats Don’t: How Animals Could Hold the Key to Unlocking Cancer Immunity in Humans. Prometheus Books, New York, NY (2016)

Zamora-Ros R, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, and Andres-Lacueva C. “High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults.” J Nutr 143: 1445–1450 (2013) 

CHAPTER 21: THE FUTURE OF MEDICINE

Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, Suematsu M, Hirose N, and von Zglinicki T. “Inflammation, but not telomere length, predicts successful ageing at extreme old age.” EBioMedicine 2: 1549–1558 (2015)

Baidal DA, Ricordi C, Garcia-Contreras M, Sonnino A, and Fabbri A. “Combination high-dose omega-3 fatty acids and high-dose cholecalciferol in new onset type 1 diabetes: A potential role in preservation of beta-cell mass.” Eur Rev Med Pharmacol Sci 20: 3313–3318 (2016)

Brand S, Holsboer-Trachsler E, Naranjo JR, and Schmidt S. “Influence of mindfulness practice on cortisol and sleep in long-term and short-term meditators.” Neuropsychobiology 65: 109–118 (2012)

Bowden Davies KA, Sprung VS, Norman JA, Thompson A, Mitchell KL, Halford JCG, Harrold JA, Wilding JPH, Kemp GJ, and Cuthbertson DJ. “Short-term decreased physical activity with increased sedentary behaviour causes metabolic derangements and altered body composition: effects in individuals with and without a first-degree relative with type 2 diabetes.” Diabetologia 61: 1282–1294 (2018)

Cadario F, Savastio S, Rizzo AM, Carrera D, Bona G, and Ricordi C. “Can Type 1 diabetes progression be halted? Possible role of high dose vitamin D and omega 3 fatty acids.” Eur Rev Med Pharmacol Sci 21: 1604–1609 (2017)

Cadario F, Savastio S, Ricotti R, Rizzo AM, Carrera D, Maiuri L, and Ricordi C. “Administration of vitamin D and high dose of omega 3 to sustain remission of type 1 diabetes.” Eur Rev Med Pharmacol Sci 22: 512–515 (2018)

Das SK, Gilhooly CH, Golden JK, Pittas AG, Fuss PJ, Cheatham RA, Tyler S, Tsay M, McCrory MA, Lichtenstein AH, Dallal GE, Dutta C, Bhapkar MV, Delany JP, Saltzman E, and Roberts SB. “Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: A 1-y randomized controlled trial.” Am J Clin Nutr 85: 1023–1030 (2007)

Day EA, Ford RJ, and Steinberg GR. “AMPK as a therapeutic target for treating metabolic diseases.” Trends Endocrinol Metab 28: 545–560 (2017)

Dohrn IM, Kwak L, Oja P, Sjöström M, and Hagströmer M. “Replacing sedentary time with physical activity: A 15-year follow-up of mortality in a national cohort.” Clin Epidemiol 10: 179–186 (2018)

Fontana L, Villareal DT, Das SK, Smith SR, Meydani SN, Pittas AG, Klein S, Bhapkar M, Rochon J, Ravussin E, and Holloszy JO. “Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: A randomized clinical trial.” Aging Cell 15: 22–27 (2016)

Gibala M. “Molecular responses to high-intensity interval exercise.” Appl Physiol Nutr Metab 34: 428–432 (2009) 

Hardie DG. “Keeping the home fires burning: AMP-activated protein kinase.” J Royal Society Interface 15: 20170774 (2018)

Harris R. Rigor Mortis. Basic Books. New York, NY (2017)

Hotamisligil GS. “Inflammation and metabolic disorders.“ Nature 444: 860–867 (2006)

Hotamisligil GS. “Inflammation, metaflammation and immunometabolic disorders.“ Nature 542: 177–185 (2017)

Hotamisligil GS. “Foundations of immunometabolism and implications for metabolic health and disease.” Immunity 47: 406–420 (2017)

Hua X, Carvalho N, Tew M, Huang ES, Herman WH, and Clarke P. “Expenditures and prices of antihyperglycemic medications in the United States: 2002-2013.” JAMA 315: 1400–1402 (2016)

Ioannidis JP. “Why most published research findings are false.” PLoS Med 2: e124 (2005)

Katsumata Y, Todoriki H, Higashiuesato Y, Yasura S, Willcox DC, Ohya Y, Willcox BJ, and Dodge HH. “Metabolic syndrome and cognitive decline among the oldest old in Okinawa: In search of a mechanism. The KOCOA project.” J Gerontol A Biol Sci Med Sci 67: 126–134 (2012)

Katsumata Y, Todoriki H, Higashiuesato Y, Yasura S, Ohya Y, Willcox DC, and Dodge HH. “Very old adults with better memory function have higher low- density lipoprotein cholesterol levels and lower triglyceride to high-density lipoprotein cholesterol ratios: KOCOA project.” J Alzheimers Dis 34: 273–279 (2013)

Kirwan AM, Lenighan YM, O’Reilly ME, McGillicuddy FC, and Roche HM. “Nutritional modulation of metabolic inflammation.” Biochem Soc Trans 45: 979–985 (2017)

Kochanek KD, Murphy SL, Xu J, and Arias E. “Mortality in the United States, 2016.” NCHS Data Brief No. 293 (2017)

Marcinko K and Steinberg GR. “The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise.” Exp Physiol 99: 1581–1585 (2014)

Marcinko K, Sikkema SR, Samaan MC, Kemp BE, Fullerton MD, and Steinberg GR. “High intensity interval training improves liver and adipose tissue insulin sensitivity.” Mol Metab 4: 903–915 (2015)

Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, Scott T, Redman LM, Stein R, Gilhooly CH, Stewart T, Robinson L, and Roberts SB. “Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: The CALERIE 2 randomized clinical trial.” JAMA Intern Med 176: 743–752 (2016)

Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, and Anderson RM. “Caloric restriction improves health and survival of rhesus monkeys.” Nat Comm 8: 14063 (2017) 

Naviaux RK. “Metabolic features and regulation of the healing cycle: A new model for chronic disease pathogenesis and treatment.” Mitochondrion 43: S1567 (2018)

McGlory C, von Allmen MT, Stokes T, Morton RW, Hector AJ, Lago BA, Raphenya AR, Smith BK, McArthur AG, Steinberg GR, Baker SK, and Phillips SM. “Failed recovery of glycemic control and myofibrillar protein synthesis with 2 wk of physical inactivity in overweight, prediabetic older adults.” J Gerontol A Biol Sci Med Sci 73: 1070–1077 (2018)

Meydani M, Das S, Band M, Epstein S, Roberts S. “The effect of caloric restriction and glycemic load on measures of oxidative stress and antioxidants in humans: Results from the CALERIE trial of human caloric restriction.” J Nutr Health Aging 15:456–60 (2011)

Nishihira J, Tokashiki T, Higashiuesato Y, Willcox DC, Mattek N, Shinto L, Ohya Y, and Dodge HH. “Associations between serum omega-3 fatty acid levels and cognitive functions among community-dwelling octogenarians in Okinawa, Japan: The KOCOA study.” J Alzheimers Dis 51: 857–866 (2016)

Prinz F, Schlange T, and Asadullah K. “Believe it or not: How much can we rely on published data on potential drug targets?” Nat Rev Drug Discov 10: 712 (2011)

Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, and Roberts SB. “A 2-year randomized controlled trial of human caloric restriction: Feasibility and effects on predictors of healthspan and longevity.” J Gerontol A Biol Sci Med Sci. 70: 1097–1104 (2015)

Redman LM, Smith SR, Burton JH, Martin CK, Il’yasova D, and Ravussin E. “Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging.” Cell Metab 27: 805–815 (2018)

Rezende LFM, Sá TH, Mielke GI, Viscondi JYK, Rey-López JP, and Garcia LMT. “All-cause mortality attributable to sitting time: Analysis of 54 countries worldwide.” Am J Prev Med 51: 253–263 (2016)

Richter EA and Ruderman NB. “AMPK and the biochemistry of exercise: Implications for human health and disease.” Biochem J 418: 261–275 (2009)

Romashkan SV, Das SK, Villareal DT, Ravussin E, Redman LM, Rochon J, Bhapkar M, and Kraus WE. “Safety of two-year caloric restriction in non-obese healthy individuals.” Oncotarget 7: 19124–19133 (2016)

Scannell JW, Blanckley A, Boldon H, and Warrington B. “Diagnosing the decline in pharmaceutical R&D efficiency.” Nat Rev Drug Discov 11: 191–200 (2012)

Sears B. “Synthetic phospholipid compounds.” U.S. Patent No. 4,426,330 (1984)

Sears B. “Delaying adverse health consequences of aging: The role of omega-3 fatty acids on inflammation and resoleomics.” CellR4 4: e2111 (2016)

Suzuki M, Willcox DC, Rosenbaum MW, and Willcox BJ. “Oxidative stress and longevity in Okinawa: An investigation of blood lipid peroxidation and tocopherol in Okinawan centenarians.” Curr Gerontol Geriatr Res. 2010: 380460 (2010)

Szarc vel Szic K, Declerck K, Vidakovic M, and Vanden Berghe W. “From inflammaging to healthy aging by dietary lifestyle choices: Is epigenetics the key to personalized nutrition?” Clin Epigenetics 7: 33 (2015)

Taylor R, Al-Mrabeh A, Zhyzhneuskaya S, Peters C, Barnes AC, Aribisala BS, Hollingsworth KG, Mathers JC, Sattar N, and Lean MEJ. “Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for beta cell recovery.” Cell Metab 28: 667 (2018)

Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, Sgonc R, and Wolfram D. “The immunology of fibrosis.” Annu Rev Immunol 31: 107–135 (2013)

Willcox DC, Willcox BJ, Todoriki H, Curb JD, and Suzuki M. “Caloric restriction and human longevity: What can we learn from the Okinawans?” Biogerontology 7: 173–177 (2006)

Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He Q, Curb JD, and Suzuki M. “Caloric restriction, the traditional Okinawan diet, and healthy aging: The diet of the world’s longest-lived people and its potential impact on morbidity and life span.” Ann N Y Acad Sci 1114: 434–455 (2007)

Willcox DC, Willcox BJ, Todoriki H, and Suzuki M. “The Okinawan diet: Health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load.” J Am Coll Nutr 28: 500S–516S (2009)

Willcox DC, Scapagnini G, and Willcox BJ. “Healthy aging diets other than the Mediterranean: A focus on the Okinawan diet.” Mech Ageing Dev 136-137: 148–162 (2014)

Willcox BJ and Willcox DC. “Caloric restriction, caloric restriction mimetics, and healthy aging in Okinawa: Controversies and clinical implications.” Curr Opin Clin Nutr Metab Care 17: 51–58 (2014)

Xu J, Murphy SL, Kochanek KD, and Arias E. “Mortality in the United States, 2015.” NCHS Data Brief No. 267 (2016)

APPENDIX C. INFLAMMATION: THE SLIGHTLY LONGER COURSE

Afonso PV, Janka-Junttila M, Lee YJ, McCann CP, Oliver CM, Aamer KA, Losert W, Cicerone MT, and Parent CA. “LTB4 is a signal-relay molecule during neutrophil chemotaxis.” Dev Cell 22: 1079–1091 (2012)

Baker RG, Hayden MS, and Ghosh S. “NF-ϰB, inflammation, and metabolic disease.” Cell Metab 13: 11–22 (2011)

Bierhaus A, Stern DM, and Nawroth PP. “RAGE in inflammation: a new therapeutic target?” Curr Opin Investig Drugs 7: 985–991 (2006) 

Cai D. “Neuroinflammation and neurodegeneration in overnutrition-induced diseases.” Trends Endocrinol Metab 24: 40–47 (2013)

Camandola S, Leonarduzzi G, Musso T, Varesio L, Carini R, Scavazza A, Chiarpotto E, Baeuerle PA, and Poli G. “Nuclear factor ϰB is activated by arachidonic acid but not by eicosapentaenoic acid.” Biochem Biophys Res Commun 229: 643–647 (1996)

Canetti C, Silva JS, Ferreira SH, and Cunha FQ. “Tumour necrosis factor-alpha and leukotriene B(4) mediate the neutrophil migration in immune inflammation.” Br J Pharmacol 134:1619–28 (2001)

Crofts CAP, Zinn C, Wheldon MC, and Schofield GM. “Hyperinsulinemia: A unifying theory of chronic disease?” Diabesity 1: 34–43 (2015)

Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, Williams AS, Lambie M, Foster TL, Liao CT, Rice CM, Greenhill CJ, Colmont CS, Hams E, Coles B, Kift-Morgan A, Newton Z, Craig KJ, Williams JD, Williams GT, Davies SJ, Humphreys IR, O’Donnell VB, Taylor PR, Jenkins BJ, Topley N, and Jones SA. “Interleukin-6 signaling drives fibrosis in unresolved inflammation.” Immunity 40: 40–50 (2014)

Gloire G, Legrand-Poels S, and Piette J. “NF-κB activation by reactive oxygen species: Fifteen years later.” Biochem Pharmacol 72: 1493–1505 (2006)

Guo H, Callaway JB, and Ting J. “Inflammasomes: Mechanism of action, role in disease and therapeutics.” Nat Med 21: 677–687 (2015)

Hardie DG. “Keeping the home fires burning: AMP-activated protein kinase.” J Royal Society Interface 15:20170774 (2018)

Hardie DG, Ross FA, and Hawley SA. “AMP-activated protein kinase: A target for drugs both ancient and modern.” Chem Bio 19: 1222–1236 (2012)

Huang S, Rutkowsky JM, Snodgrass RG, Ono-Moore KD, Schneider DA, Newman JW, Adams SH, and Hwang DH. “Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways.” J Lipid Res 53: 2002–2013 (2012)

Iwasaki A and Medzhitov R. “Control of adaptive immunity by the innate immune system.” Nat Immunol 16: 343–353 (2015)

Kawai T and Akira S. “The role of pattern-recognition receptors in innate immunity: Update on toll-like receptors.” Nat Immunol 11: 373–384 (2010)

Sánchez-Galán E, Gómez-Hernández A, Vidal C, Martín-Ventura JL, Blanco-Colio LM, Muñoz-García B, Ortega L, Egido J, and Tuñón J. “Leukotriene B4 enhances the activity of nuclear factor-kappaB pathway through BLT1 and BLT2 receptors in atherosclerosis.” Cardiovasc Res 81: 216–225 (2009)

Sen R and Baltimore D. “Multiple nuclear factors interact with the immunoglobulin enhancer sequences.” Cell 46: 705–716. (1986)

Serhan CN, Ward PA, Gilroy DW, and Samir S. Fundamentals of Inflammation. Cambridge University Press. Cambridge, UK (2010)

Serhan CN. “Pro-resolving lipid mediators are leads for resolution physiology.” Nature 510: 92–101 (2014)

Tóbon-Velasco JC, Cuevas E, and Torres-Ramos MA. “Receptor for AGEs (RAGE) as mediator of NF-ϰB pathway activation in neuroinflammation and oxidative stress.” CNS Neurol Disord Drug Targets 13: 1615–1626 (2014)

Trowbridge HO and Emling RC. Inflammation: A Review of the Process. Quintessence Publising. Chicago, IL (1997)

Volchenkov R, Sprater F, Vogelsang P, and Appel S. “The 2011 Nobel Prize in physiology or medicine.” Scand J Immunol 75: 1–4 (2012)

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, and Ferrante AW. “Obesity is associated with macrophage accumulation in adipose tissue.” J Clin Invest 112: 1796–1808 (2003)

Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, Sgonc R, and Wolfram D. “The immunology of fibrosis.” Annu Rev Immunol 31: 107–135 (2013)

Yan SF, Ramasamy R, and Schmidt AM. “Mechanisms of disease: Advanced glycation end-products and their receptor in inflammation and diabetes complications.” Nat Clin Pract Endocrinol Metab 4: 285–293 (2008)

Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, and Cohen RA. “Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL- receptor-deficient mice.” Diabetes 55: 2180–2191 (2006)

Zhang Q, Lenardo MJ, and Baltimore D. “30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology.” Cell 168: 37–57 (2017)

Zhang X, Zhang G, Zhang H, Karin M, Bai H, and Cai D. “Hypothalamic IKKbeta/ NF-κB and ER stress link overnutrition to energy imbalance and obesity.” Cell 135: 61–73 (2008)

APPENDIX D. METABOLISM OF ESSENTIAL FATTY ACIDS, EICOSANOIDS, AND RESOLVINS

Brenner RR. “Nutritional and hormonal factors influencing desaturation of essential fatty acids.” Prog Lipid Res 20: 41–47 (1981)

Serhan CN. “Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology.” Mol Aspects Med 58: 1–11 (2017)

Serhan CN, Chiang N, and Dalli J. “The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution.” Semin Immunol 27: 200– 215 (2015)

Spite M, Clària J, and Serhan CN. “Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases.” Cell Metab 19: 21–36 (2014)

Willis AL. Handbook of Eicosanoids. CRC Press. Boca Raton, FL (1987)

APPENDIX E. ENERGY-SENSING GENE TRANSCRIPTION FACTORS

Ford RJ Desjardins EM, and Steinberg GR. “Are SIRTI activators another indirect method to increase AMPK for beneficial effects on aging and metabolic syndrome?” EBioMedicine 19: 16–17 (2017)

Hardie DG, Ross FA, and Hawley SA. “AMP-activate protein kinase: A target for drugs both ancient and modern.” Chem Bio 19: 1222–1236 (2012)

Hardie DG. “Keeping the home fires burning: AMP-activated protein kinase.” J Royal Society Interface. 15: 20170774 (2018)

Park S-J, Ahmad F, Um JH, Brown AL, Xu X, Kang H, Ke H, Feng X, Ryall J, Philp A, Schenk S, Kim MK, Sartorelli V, and Chung JH. “Specific Sirt1 activator- mediated improvement in glucose homeostatsis requires Sirt 1-independent activation of AMPK.” EBioMedicine 18: 128–138 (2017)

Peng L, Li ZR, Green RS, Holzman IR, Lin J. “Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers.” J Nutr 139: 1619–1625 (2009)

Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, and Sinclair DA. “SIRT-1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function.” Cell Metab 15: 675–690 (2012)

Rahnasto-Rilla M, Tyni J, Huovinen M, Jarho E, Kulikowicz T, Ravichandran S, A Bohr V, Ferrucci L, Lahtela-Kakkonen M, and Moaddel R. “Natural polyphenols as sirtuin 6 modulators.” Sci Rep 8:4163 (2018)

Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, and Ido Y. “AMPK and SIRT1: A long-standing partnership?” Am J Physiol Endocrinol Metabol 298: E751–E760 (2010)

Sun X and Zhu MJ. “AMP-activated protein kinase: A therapeutic target in intestinal diseases. Open Biol 7: 170104 (2017)

Sun X, Yang Q, Rogers CJ, Du M, and Zhu MJ. “AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression.” Cell Death Differ 24: 819–831 (2017)

Zhang L, Li J, Young LH, and Caplan MJ. “AMP-activated protein kinase regulates the assembly of epithelial tight junctions.” Proc Natl Acad Sci U S A. 103:17272– 17227 (2006)

APPENDIX F. AMP KINASE AND MITOCHONDRIA

Chan K, Truong D, Shangari N, and O’Brien PJ. “Drug-induced mitochondrial toxicity.” Expert Opin Drug Metab Toxicol 1: 655–669 (2005)

Davinelli S, Corbi G, Righetti S, Sears B, Olarte HH, Grassi D, and Scapagnini “Cardioprotection by cocoa polyphenols and n-3 fatty acids: A disease-prevention perspective on aging-associated cardiovascular risk.” J Med Food 21: 1060–1069 (2018)

Duarte DA, Rosales MA, Papadimitriou A, Silva KC, Amancio VH, Mendonça JN, Lopes NP, de Faria JB, and de Faria JM. “Polyphenol-enriched cocoa protects the diabetic retina from glial reaction through the sirtuin pathway.” J Nutr Biochem 26: 64–74 (2015)

Herzig S and Shaw RJ. “AMPK: Guardian of metabolism and mitochondrial homeostasis.” Nat Rev Mol Cell Biol 19: 121–135 (2018)

Hwang JT, Kwon DY, and Yoon SH. “AMP-activated protein kinase: A potential target for the diseases prevention by natural occurring polyphenols.” N Biotechnol 26: 17–22 (2009)

Know, L. Life: The Epic Story of Our Mitochondria. Friesen Press. Victoria, BC, Canada. (2014)

Laker RC, Drake JC, Wilson RJ, Lira VA, Lewellen BM, Ryall KA, Fisher CC, Zhang M, Saucerman JJ, Goodyear LJ, Kundu M, and Yan Z. “AMPK phosphorylation of ULK1 is required for targeting of mitochondria to lysosomes in exercise- induced mitophagy.” Nat Commun 15: 548 (2017)

Lane N. Power, Sex, and Suicide: Mitochondria and the Meaning of Life. Oxford University Press. Oxford, UK (2005)

Krishnamoorthy RM and Carani Venkatraman A. “Polyphenols activate energy sensing network in insulin resistant models.” Chem Biol Interact 275: 95–107 (2017)

Rieusset J. “Role of endoplasmic reticulum-mitochondria communication in type 2 diabetes.” Adv Exp Med Biol 997: 171–186 (2017)

Scatena R. “Mitochondria and drugs.” Adv Exp Med Biol 942: 329–346 (2012)

Sears B and Ricordi C. “Role of fatty acids and polyphenols in inflammatory gene transcription and their impact on obesity, metabolic syndrome and diabetes.” Eur Rev Med Pharmacol Sci 16: 1137–54 (2012)

Sears B. “Anti-inflammatory diets.” J Am Coll Nutr 34 Suppl 1:14–21 (2015)

Tagaya M and Arasaki K. “Regulation of mitochondrial dynamics and autophagy by the mitochondria-associated membrane.” Adv Exp Med Biol 997: 33–47 (2017)

Tang BL. “Sirt1 and the mitochondria.” Mol Cells 39: 87–95 (2016)

Thoudam T, Jeon JH, Ha CM, and Lee IK. “Role of mitochondria-associated endoplasmic reticulum membrane in inflammation-mediated metabolic diseases.” Mediators Inflamm 2016: 1851420 (2016)

Tubbs E, Theurey P, Vial G, Bendridi N, Bravard A, Chauvin MA, Ji-Cao J, Zoulim F, Bartosch B, Ovize M, Vidal H, and Rieusset J. “Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance.” Diabetes 63: 3279– 3294 (2014)

Varga ZV, Ferdinandy P, Liaudet L, and Pacher P. “Drug-induced mitochondrial dysfunction and cardiotoxicity.” Am J Physiol Heart Circ Physiol 309: H1453– 467 (2015)

Weir HJ, Yao P, Huynh FK, Escoubas CC, Goncalves RL, Burkewitz K, Laboy R, Hirschey MD, and Mair WB. “Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling.” Cell Metab 5: 884– 896 (2017)

APPENDIX G. GUT PHYSIOLOGY

Anderson SC. The Psychobitoic Revolution. National Geographic Books. Washington DC (2017)

Anhê FF, Roy D, Pilon G, Dudonné S, Matamoros S, Varin TV, Garofalo C, Moine Q, Desjardins Y, Levy E, and Marette A. “A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in gut microbiota of mice.” Gut 64: 872–883 (2015)

Asarian L and Bächler T. “Neuroendocrine control of satiation.” Horm Mol Biol Clin Investig 19: 163–192 (2014)

Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, Sjostrom SL, Szewczykowska M, Jackowska T, Dos Remedios C, Malm T, Andrä M, Jashari R, Nyengaard JR, Possnert G, Jovinge S, Druid H, and Frisén J. “Dynamics of cell generation and turnover in the human heart.” Cell 161: 1566–1575 (2015)

Blasser MJ. Missing Microbes. Henry Holt. New York, NY (2014)

Bliss ES and Whiteside E. “The gut-brain axis, the human gut microbiota and their integration in the development of obesity.” Front Physiol 9: 900 (2018)

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, and Burcelin R. “Metabolic endotoxemia initiates obesity and insulin resistance.” Diabetes 56: 1761–1772 (2007)

Caesasr R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, and Backhed F. “Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling.” Cell Metabol 22: 1–11 (2015)

Chambers ES, Morrison DJ, and Frost G. “Control of appetite and energy intake by SCFA: What are the potential underlying mechanisms?” Proc Nutr Soc 74: 328–336 (2015)

Chio CC, Baba T, and Black KL. “Selective blood-tumor barrier disruption by leukotrienes.” J Neurosurg 77: 407–410 (1992)

Christiansen CB, Gabe MBN, Svendsen B, Dragsted LO, Rosenkilde MM, and Holst JJ. “The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon.” Am J Physiol Gastrointest Liver Physiol 315: G53– G65 (2018) 

Chronaiou A, Tsoli M, Kehagias I, Leotsinidis M, Kalfarentzos F, and Alexandrides TK. “Lower ghrelin levels and exaggerated postprandial peptide-YY, glucagon- like peptide-1, and insulin responses, after gastric fundus resection, in patients undergoing Roux-en-Y gastric bypass: A randomized clinical trial.” Obes Surg 22: 1761–1770 (2012)

Collen A. 10% Human. Harper Collins. New York, NY (2015)

Cornick S, Tawiah A, and Chadee K. “Roles and regulation of the mucus barrier in the gut.” Tissue Barriers 3: e982426 (2015)

Delcour JA, Aman P, Courtin CM, Hamaker BR, and Verbeke K. “Prebiotics, fermentable dietary fiber, and health claims.” Adv Nutr 7: 1–4 (2016)

Derrien M. “Akkermansia muciniphila, a human intestinal mucin-degrading bacterium.” Int J Systematic and Evolutionary Microbiology 54: 1469–1476 (2004)

Daud NM, Ismail NA, Thomas EL, Fitzpatrick JA, Bell JD, Swann JR, Costabile A, Childs CE, Pedersen C, Goldstone AP, and Frost GS. “The impact of oligofructose on stimulation of gut hormones, appetite regulation and adiposity.” Obesity 22: 1430–1438 (2014)

de Vogel-van den Bosch HM, Bünger M, de Groot PJ, Bosch-Vermeulen H, Hooiveld GJ, and Müller M. “PPARƴ-mediated effects of dietary lipids on intestinal barrier gene expression.” BMC Genomics 9: 231 (2008)

Everard A and Cani PD. “Gut microbiota and GLP-1.” Rev Endocr Metab Disord 15: 189–196 (2014)

Fasano A. “Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.” Physiol Rev 91: 151–175 (2011)

Fredricks D. The Human Microbiota: How Microbial Communities Affect Health and Disease. Wiley-Blackwell. New York, NY (2013)

Gershon MD. The Second Brain. Harper Collins. New York, NY (1999)

Goodman BE. “Insights into digestion and absorption of major nutrients in humans.” Adv Physiol Educ 34: 44–53 (2010)

Greiner TU and Bäckhed F. “Microbial regulation of GLP-1 and L-cell biology.” Mol Metab 5: 753–758 (2016)

Grossi E and Pace F eds. Human Nutrition from the Gastroenterologist’s Perspective. Springer. New York, NY (2016)

Kaliannan K, Wang B, Xiang-Yong L, Kim K-J, and Kang JX. “A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia.” Sci Reports 5: 112276 (2015)

Kimura R, Takahashi N, Lin S, Goto T, Murota K, Nakata R, Inoue H, and Kawada “DHA attenuates postprandial hyperlipidemia via activating PPARƴ in intestinal epithelial cells.” J Lipid Res 54: 3258–3268 (2013)

Konturek SJ and Brzozowski T. “Role of leukotrienes and platelet activating factor in gastric mucosal damage and repair.” J Physiol Pharmacol 42:107–133 (1991)

Larraufie P, Martin-Gallausiaux C, Lapaque N, Dore J, Gribble FM, Reimann F, and Blottiere HM. “SCFAs strongly stimulate PYY production in human enteroendocrine cells.” Sci Rep 8: 74 (2018)

Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Stärkel P, Windey K, Tremaroli V, Bäckhed F, Verbeke K, de Timary P, and Delzenne NM. “Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol- dependence severity.” Proc Natl Acad Sci U S A 111: E4485–4493 (2014)

López-Moreno J, García-Carpintero S, Jimenez-Lucena R, Haro C, Rangel-Zúñiga OA, Blanco-Rojo R, Yubero-Serrano EM, Tinahones FJ, Delgado-Lista J, Pérez- Martínez P, Roche HM, López-Miranda J, and Camargo A. “Effect of dietary lipids on endotoxemia influences postprandial inflammatory response.” J Agric Food Chem 65: 7756–7763 (2017)

Lyte M and Cryan JF. Microbial Endocrinology: The Microbiota-Gut-Brain Axis. Springer. New York, NY (2014)

Masumoto S, Terao A, Yamamoto Y, Mukai T, Miura T, and Shoji T. “Non- absorbable apple procyandian prevent obesity associated with gut microbial and metabolomics changes.” Sci Reports 6: 31208 (2016)

Mayer E. The Mind-Gut Connection. Harper Wave. New York, NY (2016)

Nettleton JE, Reimer RA, and Shearer J. “Reshaping the gut microbiota: Impact of low-calorie sweeteners and the link to insulin resistance?” Physiol Behav164 (Pt B): 488–493 (2016)

Pelaseyed T, Bergström JH, Gustafsson JK, Ermund A, Birchenough GM, Schütte A, van der Post S, Svensson F, Rodríguez-Piñeiro AM, Nyström EE, Wising C, Johansson ME, and Hansson GC. “The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system.” Immunol Rev 260: 8–20 (2014)

Pepino MY, Tiemann CD, Patterson BW, Wice BM, and Klein S. “Sucralose affects glycemic and hormonal responses to an oral glucose load.” Diabetes Care 36: 2530–2535 (2013)

Pepino MY. “Metabolic effects of non-nutritive sweeteners.” Physiol Behav 152 (Pt B): 450–5 (2016)

Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR, and Frost G. “The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents.” Int J Obes 39: 424–429 (2015)

Roach M. Gulp. W.W. Norton and Company. New York, NY (2013)

Roopchand DE, Carmody RN, Kuhn P, Moskal K, Rojas-Silva, Turnbaugh PJ, and Raskin I. “Dietary polyphenols promote growth of gut bacterium Akkermansia muninphila and attenuate high-fat diet-induced metabolic syndrome.” Diabetes 64: 2847–2858 (2015)

Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, Gomis R, Claret M, and Cani PD. “Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders in mice.” Sci Reports 5: 16643 (2015)

Schroeder N, Marquart LF, and Gallaher DD. “The role of viscosity and fermentability of dietary fibers on satiety- and adiposity-related hormones in rats.” Nutrients 5: 2093–2113 (2013)

Slavin J. “Fiber and prebiotics.” Nutrients 5: 1417–1435 (2013)

Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, and Sonnenburg JL. “Diet-induced extinctions in the gut microbiota compound over generations.” Nature 529: 212–215 (2016)

Sonneburg J and Sonnenburg E. The Good Gut. Penguin Books. New York, NY (2016)

Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, and Frisén J. “Retrospective birth dating of cells in humans.” Cell 122: 133–143 (2005)

Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T, Concha H, Hassan M, Rydén M, Frisén J, and Arner P. “Dynamics of fat cell turnover in humans.” Nature 453: 783–787 (2008)

Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, and Frisén J. “Dynamics of hippocampal neurogenesis in adult humans.” Cell 153: 1219–1227 (2013)

Spreckley E and Murphy KG. “The L-cell in nutritional sensing and the regulation of appetite.” Front Nutr 2: 23 (2015)

Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, and Elinav E. “Artificial sweeteners induce glucose intolerance by altering the gut microbiota.” Nature 514: 181–186 (2014)

van der Klaauw AA, Keogh JM, Henning E, Trowse VM, Dhillo WS, Ghatei MA, and Farooqi IS. “High protein intake stimulates postprandial GLP-1 and PYY release.” Obesity 21: 1602–1607 (2013)

Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, Salim Rasoel S, Tκth J, Holvoet L, Farré R, Van Oudenhove L, Boeckxstaens G, Verbeke K, and Tack J. “Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism.” Gut 63: 1293–1299 (2014)

Tuohy K and Del Rio D. Diet-Microbe Interactions in the Gut. Academic Press. London, UK (2015)

Wrangham R. Cooking with Fire. Basic Books. New York, NY (2010)

Yeomans MR, Tepper BJ, Rietzschel J, and Prescott J. “Human hedonic responses to sweetness: Role of taste genetics and anatomy.” Physiol Behav 91: 264–273 (2007)

Zanchi D, Depoorter A, Egloff L, Haller S, Mählmann L, Lang UE, Drewe J, Beglinger C, Schmidt A, and Borgwardt S. “The impact of gut hormones on the neural circuit of appetite and satiety: A systematic review.” Neurosci Biobehav Rev 80: 457–475 (2017)