The Longevity Solution

by Jason Fung

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  13. Pak, J. W., et al. “Rebuttal to Jacobs: The Mitochondrial Theory of Aging: Alive and Well.” Aging Cell 2, no. 1 (2003): 9–10.

  14. Rasmussen, U. F., et al. “Experimental Evidence Against the Mitochondrial Theory of Aging. A Study of Isolated Human Skeletal Muscle Mitochondria.” Experimental Gerontology 38, no. 8 (2003): 877–86.

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  17. Ibid.

  18. Feinendegen, L. E. “Evidence for Beneficial Low Level Radiation Effects and Radiation Hormesis.” The British Journal of Radiology 78, no. 925 (2005): 3–7.

  19. Ibid.

  20. Miller, R. A., et al. “Big Mice Die Young: Early Life Body Weight Predicts Longevity in Genetically Heterogeneous Mice.” Aging Cell no. 1 (2002): 22–9.

  21. He, Q., et al. “Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry.” PLoS One 9, no. 5 (2014): e94385.

  22. Blagosklonny, M. V. “Big Mice Die Young but Large Animals Live Longer.” Aging (Albany, NY) 5, no. 4 (2013): 227–33.

  Chapter 2

  1. Masoro, E. J. “Overview of Caloric Restriction and Ageing.” Mechanisms of Ageing Development 126, no. 9 (2005): 913–22.

  2. McCay, C. M., et al. “The Effect of Retarded Growth upon the Length of Life Span and upon the Ultimate Body Size.” The Journal of Nutrition 10, no. 1 (1935): 63–79.

  3. Richardson, A., et al. “Significant Life Extension by Ten Percent Dietary Restriction.” Annals of the New York Academy of Science 1363 (2016): 11–7.

  4. Tannenbaum, A. “The Genesis and Growth of Tumors II. Effect of Caloric Restriction Per Se.” Cancer Research 2, no. 7 (1942): 460–7.

  5. Carlson, A. J., and F. Hoelzel. “Apparent Prolongation of the Life Span of Rats by Intermittent Fasting.” Journal of Nutrition 31 (1946): 363–75.

  6. Ross, M. H. “Protein, Calories and Life Expectancy.” Federation Proceedings 18 (1959): 1190–207.

  7. Iwasaki, K., et al. “The Influence of Dietary Protein Source on Longevity and Age-Related Disease Processes of Fischer Rats.” Journal of Gerontology 43, no. 1 (1988): B5–12.

  8. Redman, L. M., and E. Ravussin. “Caloric Restriction in Humans: Impact on Physiological, Psychological, and Behavioral Outcomes.” Antioxidants & Redox Signaling 14, no. 2 (2011): 275–87; Suzuki, M., B. J. Wilcox, and C. D. Wilcox. “Implications from and for Food Cultures for Cardiovascular Disease: Longevity.” Asia Pacific Journal of Clinical Nutrition 10, no. 2 (2001): 165–71.

  9. Stanfel, M. N., et al. “The TOR Pathway Comes of Age.” Biochimica et Biophysica Acta 1790, no. 10 (2009): 1067–74.

  10. McDonald, R. B., and J. J. Ramsey. “Honoring Clive McCay and 75 Years of Calorie Restriction Research.” Journal of Nutrition 140, no. 7 (2010): 1205–10.

  11. Bluher, M. “Fat Tissue and Long Life.” Obesity Facts 1, no. 4 (2008): 176–82.

  12. Adelman, R., R. L. Saul, and B. N. Ames. “Oxidative Damage to DNA: Relation to Species Metabolic Rate and Life Span.” Proceedings of the National Academy of Sciences of the United States of America 85, no. 8 (1988): 2706–8.

  13. Hulbert, A. J., et al. “Life and Death: Metabolic Rate, Membrane Composition, and Life Span of Animals.” Physiological Reviews 87, no. 4 (2007): 1175–213.

  14. Mariotti, S., et al. “Complex Alteration of Thyroid Function in Healthy Centenarians.” Journal of Clinical Endocrinology and Metabolism 77, no. 5 (1993): 1130–4.

  15. See note 1 above.

  16. Paolisso, G., et al. “Body Composition, Body Fat Distribution, and Resting Metabolic Rate in Healthy Centenarians.” American Journal of Clinical Nutrition 62, no. 4 (1995): 746–50.

  17. Lee, S. J., C. T. Murphy, and C. Kenyon. “Glucose Shortens the Life Span of C. elegans by Downregulating DAF-16/FOXO Activity and Aquaporin Gene Expression.” Cell Metabolism 10, no. 5 (2009): 379–91.

  18. Masoro, E. J., et al. “Dietary Restriction Alters Characteristics of Glucose Fuel Use.” Journal of Gerontology 47, no. 6 (1992): B202–8.

  19. Kenyon, C., et al. “A C. elegans Mutant That Lives Twice as Long as Wild Type.” Nature 366, no. 6454 (1993): 461–4.

  20. “Cynthia Kenyon.” https://en.wikipedia.org/wiki/Cynthia_Kenyon.

  21. Taubes, G. “Rare Form of Dwarfism Protects Against Cancer.” Discover, March 27, 2013. Accessed at http://discovermagazine.com/2013/april/19-double-edged-genes.

  22. Blagosklonny, M. V. “Calorie Restriction: Decelerating mTOR-Driven Aging from Cells to Organisms (Including Humans).” Cell Cycle 9, no. 4 (2010): 683–8.

  23. Cuervo, A. M., et al. “Autophagy and Aging: The Importance of Maintaining ‘Clean’ Cells.” Autophagy 1, no. 3 (2005): 131–40.

  24. Jia, K., and B. Levine. “Autophagy Is Required for Dietary Restriction-Mediated Life Span Extension in C. elegans.” Autophagy 3, no. 6 (2007): 597–9; Melendez, A., et al. “Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans.” Science 301, no. 5638 (2003): 1387–91.

  25. Alvers, A. L., et al. “Autophagy Is Required for Extension of Yeast Chronological Life Span by Rapamycin.” Autophagy 5, no. 6 (2009): 847–9.

  26. Hardie, D. G., F. A. Ross, and S. A. Hawley. “AMPK: A Nutrient and Energy Sensor That Maintains Energy Homeostasis.” Nature Reviews Molecular Cell Biology 13, no. 4 (2012): 251–62.

  27. Canto, C., and J. Auwerx. “Calorie Restriction: Is AMPK a Key Sensor and Effector?” Physiology (Bethesda) 26, no. 4 (2011): 214–24.

  28. Lyons, C., and H. Roche. “Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation.” International Journal of Molecular Sciences 19, no. 10 (2018): 3092.

  29. Anson, R. M., B. Jones, and R. de Cabod. “The Diet Restriction Paradigm: A Brief Review of th
e Effects of Every-Other-Day Feeding.” Age (Dordr) 27, no. 1 (2005): 17–25.

  30. Hambly, C., et al. “Repletion of TNFalpha or Leptin in Calorically Restricted Mice Suppresses Post-Restriction Hyperphagia.” Disease Model Mechanisms 5, no. 1 (2012): 83–94.

  31. Goodrick, C. L., et al. “Effects of Intermittent Feeding upon Growth and Life Span in Rats.” Gerontology 28, no. 4 (1982): 233–41.

  32. Goldberg, E. L., et al. “Lifespan-Extending Caloric Restriction or mTOR Inhibition Impair Adaptive Immunity of Old Mice by Distinct Mechanisms.” Aging Cell 14, no. 1 (2015): 130–8.

  33. Ingram, D. K., et al. “Calorie Restriction Mimetics: An Emerging Research Field.” Aging Cell 5, no. 2 (2006): 97–108.

  Chapter 3

  1. “Did a Canadian Medical Expedition Lead to the Discovery of an Anti-Aging Pill?” Bloomberg News, February 12, 2015. Accessed at https://business.financialpost.com/news/did-a-canadian-medical-expedition-lead-to-the-discovery-of-an-anti-aging-pill.

  2. Mohsin, N., et al. “Complete Regression of Visceral Kaposi’s Sarcoma After Conversion to Sirolimus.” Experimental and Clinical Transplantation 3, no. 2 (2005): 366–9.

  3. Blagosklonny, M. V. “Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition.” Cell Cycle 5, no. 18 (2006): 2087–102.

  4. Ortman, J., V. Velkoff, and H. Hogan. “An Aging Nation: The Older Population in the United States.” May 2014. Accessed at www.census.gov/prod/2014pubs/p25-1140.pdf.

  5. Christensen, K., et al. “Ageing Populations: The Challenges Ahead.” The Lancet 374, no. 9696 (2009): 1196–208; Drachman, D. A. “Aging of the Brain, Entropy, and Alzheimer Disease.” Neurology 67, no. 8 (2006): 1340–52; Holroyd, C., C. Cooper, and E. Dennison. “Epidemiology of Osteoporosis.” Best Practice & Research: Clinical Endocrinology & Metabolism 22, no. 5 (2008): 671–85.

  6. Nair, S., and J. Ren. “Autophagy and Cardiovascular Aging: Lesson Learned from Rapamycin.” Cell Cycle 11, no. 11 (2012): 2092–9.

  7. Powers, R. W., 3rd, et al. “Extension of Chronological Life Span in Yeast by Decreased TOR Pathway Signaling.” Genes & Development 20, no. 2 (2006): 174–84.

  8. Robida-Stubbs, S., et al. “TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO.” Cell Metabolism 15, no. 5 (2012): 713–24.

  9. Bjedov, I., et al. “Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila Melanogaster.” Cell Metabolism 11, no. 1 (2010): 35–46.

  10. Harrison, D., et al. “Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice.” Nature 460 (2009): 392–5.

  11. Halford, B. “Rapamycin’s Secrets Unearthed.” Chemical & Engineering News 94, no. 29 (2016): 26–30.

  12. Urfer, S. R., et al. “A Randomized Controlled Trial to Establish Effects of Short-Term Rapamycin Treatment in 24 Middle-Aged Companion Dogs.” Geroscience 39, no. 2 (2017): 117–27.

  13. Lelegren, M., et al. “Pharmaceutical Inhibition of mTOR in the Common Marmoset: Effect of Rapamycin on Regulators of Proteostasis in a Non-Human Primate.” Pathobiology of Aging & Age Related Diseases 6 (2016): 31793.

  14. Spilman, P., et al. “Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-Beta Levels in a Mouse Model of Alzheimer’s Disease.” PLoS One 5, no. 4 (2010): e9979.

  15. Majumder, S., et al. “Lifelong Rapamycin Administration Ameliorates Age-Dependent Cognitive Deficits by Reducing IL-1beta and Enhancing NMDA Signaling.” Aging Cell 11, no. 2 (2012): 326–35.

  16. Liu, Y., et al. “Rapamycin-Induced Metabolic Defects Are Reversible in Both Lean and Obese Mice.” Aging (Albany NY) 6, no. 9 (2014): 742–54.

  17. Kolosova, N. G., et al. “Prevention of Age-Related Macular Degeneration-Like Retinopathy by Rapamycin in Rats.” American Journal of Pathology 181, no. 2 (2012): 472–7.

  18. Halloran, J., et al. “Chronic Inhibition of Mammalian Target of Rapamycin by Rapamycin Modulates Cognitive and Non-Cognitive Components of Behavior Throughout Lifespan in Mice.” Neuroscience 223 (2012): 102–13; Tsai, P. T., et al. “Autistic-Like Behaviour and Cerebellar Dysfunction in Purkinje Cell Tsc1 Mutant Mice.” Nature 488, no. 7413 (2012): 647–51; Perl, A. “mTOR Activation is a Biomarker and a Central Pathway to Autoimmune Disorders, Cancer, Obesity, and Aging.” Annals of the New York Academy of Science 1346, no. 1 (2015): 33–44.

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  20. Mendelsohn, A. R., and J. W. Larrick. “Dissecting Mammalian Target of Rapamycin to Promote Longevity.” Rejuvenation Research 15, no. 3 (2012): 334–7.

  21. Johnston, O., et al. “Sirolimus Is Associated with New-Onset Diabetes in Kidney Transplant Recipients.” Journal of the American Society of Nephrology 19, no. 7 (2008): 1411–8.

  22. Lamming, D. W. “Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond.” Cold Spring Harbor Perspectives in Medicine 6, no. 5 (2016).

  23. See note 20 above.

  24. Arriola Apelo, S. I., et al. “Alternative Rapamycin Treatment Regimens Mitigate the Impact of Rapamycin on Glucose Homeostasis and the Immune System.” Aging Cell 15, no. 1 (2016): 28–38.

  25. See note 11 above.

  26. Carlson, A. J., and F. Hoelzel. “Growth and Longevity of Rats Fed Omnivorous and Vegetarian Diets.” Journal of Nutrition 34, no. 1 (1947): 81–96.

  27. Siri-Tarino, P. W., et al. “Meta-Analysis of Prospective Cohort Studies Evaluating the Association of Saturated Fat with Cardiovascular Disease.” American Journal of Clinical Nutrition 91, no. 3 (2010): 535–46.

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  30. Lee, C., and V. Longo. “Dietary Restriction with and Without Caloric Restriction for Healthy Aging.” F1000Research 5 (2016).

  31. Longo, V. D., and L. Fontana. “Calorie Restriction and Cancer Prevention: Metabolic and Molecular Mechanisms.” Trends in Pharmacological Sciences 31, no. 2 (2010): 89–98.

  32. Fontana, L., et al. “Long-Term Effects of Calorie or Protein Restriction on Serum IGF-1 and IGFBP-3 Concentration in Humans.” Aging Cell 7, no. 5 (2008): 681–7.

  33. Huang, C. H., et al. “EGCG Inhibits Protein Synthesis, Lipogenesis, and Cell Cycle Progression Through Activation of AMPK in p53 Positive and Negative Human Hepatoma Cells.” Molecular Nutrition & Food Research 53, no. 9 (2009): 1156–65.

  34. Pazoki-Toroudi, H., et al. “Targeting mTOR Signaling by Polyphenols: A New Therapeutic Target for Ageing.” Ageing Research Reviews 31 (2016): 55–66.

  35. Chiu, C. T., et al. “Hibiscus Sabdariffa Leaf Polyphenolic Extract Induces Human Melanoma Cell Death, Apoptosis, and Autophagy.” Journal of Food Science 80, no. 3 (2015): H649–58; Zhang, L., et al. “Polyphenol-Rich Extract of Pimenta Dioica Berries (Allspice) Kills Breast Cancer Cells by Autophagy and Delays Growth of Triple Negative Breast Cancer in Athymic Mice.” Oncotarget 6, no. 18 (2015): 16379–95; Syed, D. N., et al. “Pomegranate Extracts and Cancer Prevention: Molecular and Cellular Activities.” Anti-Cancer Agents in Medicinal Chemistry 13, no. 8 (2013): 1149–61.

  36. Pazoki-Toroudi, H., et al. “Targeting mTOR Signaling by Polyphenols: A New Therapeutic Target for Ageing.” Ageing Research Reviews 31 (2016): 55–66; Morselli, E., et al. “Caloric Restriction and Resveratrol Promote Longevity Through the Sirtuin-1-Dependent Induction of Autophagy.” Cell Death Discovery 1 (2010): e10; Park, S. J., et al. “Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting
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  39. Bannister, C. A., et al. “Can People with Type 2 Diabetes Live Longer Than Those Without? A Comparison of Mortality in People Initiated with Metformin or Sulphonylurea Monotherapy and Matched, Non-Diabetic Controls.” Diabetes, Obesity and Metabolism 16, no. 11 (2014): 1165–73.

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  43. Grandison, R. C., M. D. Piper, and L. Partridge. “Amino-Acid Imbalance Explains Extension of Lifespan by Dietary Restriction in Drosophila.” Nature 462, no. 7276 (2009): 1061–4.

  44. Kim, E., and K. L. Guan. “RAG GTPases in Nutrient-Mediated TOR Signaling Pathway.” Cell Cycle 8, no. 7 (2009): 1014–8.

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  46. Liu, K. A., et al. “Leucine Supplementation Differentially Enhances Pancreatic Cancer Growth in Lean and Overweight Mice.” Cancer Metabolism 2, no. 1 (2014): 6.

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