Rapamycin: Rapamycin, Mtor, Autophagy & Treating Mtor Syndrome (Paperback)

Rapamycin: Rapamycin, Mtor, Autophagy & Treating Mtor Syndrome By Ross Pelton Cover Image


RAPAMYCIN: A Quantum Leap in Life Extension

Rapamycin, mTOR, Autophagy and Treating mTOR Syndrome

by Ross Pelton

Rapamycin is an FDA-approved drug that is ushering in a new era of life extension. However, to be clear, rapamycin is not approved by the FDA as a life extension drug. In September 1999 rapamycin received FDA approval as an immunosuppressant drug to prevent organ transplant rejection and also, two rapamycin analogs (rapalogs), temsirolimus (Torisel) and everolimus (Afinitor) have gained FDA approval for the treatment of various forms of cancer. However, rapamycin's approval as an immunosuppressant and as a cancer chemotherapy agent has inhibited its acceptance by physicians as a life extension drug.

Treatment with rapamycin has resulted in significant increases in lifespan in animal models including yeast, worms, fruit flies, and mice. Animals get many of the same diseases that humans develop. Results from animal studies reveal that rapamycin slows down the onset of many age-related diseases. In addition to improving animals' health, treatment with rapamycin has produced life extensions ranging from 25-60%.

Discovery of Rapamycin

Rapamycin is a compound that is produced by a strain of bacteria named Streptomyces hygroscopicus.This bacterium was discovered from a soil sample taken during a scientific expedition to Easter Island in 1964. The purpose of that expedition was to search for new compounds that might express antifungal and/or antibiotic properties. Rapamycin expressed strong antifungal activity. However, efforts to develop rapamycin as an antifungal drug were discontinued when it was discovered to have potent immunosuppressive activity.

Rapamycin also exhibited anti-proliferative properties, which prompted scientists to send samples of rapamycin to the National Cancer Institute (NCI). Tests conducted there revealed two remarkable findings. The first revelation was that rapamycin suppressed the growth in a variety of solid tumors.

The second finding was the discovery that rapamycin appeared to be a totally new type of anticancer drug because it functioned by inhibiting cancer growth (cytostatic) rather than by killing cancer cells (cytotoxic). Cytotoxic chemotherapy drugs cause a wide range of side effects because they damage other rapidly dividing cells in the body. Rapamycin's activity against solid tumors plus its cytostatic mechanism of action motivated the NCI to elevate rapamycin to "priority drug" status in order to accelerate additional research.

Rapamycin's Mechanism of Action

Over the past 25 years, research into rapamycin's mechanism of action has resulted in the discovery of a new understanding of cellular biology and the aging process. This research has revealed that two mechanisms named mTOR and autophagy, which are found inside every cell, are critical regulators of cellular metabolism.

mTOR and autophagy are counterbalancing mechanisms that regulate the health and aging process of all living organisms. In my mind, the mTOR/Autophagy story is even more important than the story about rapamycin. The discovery and understanding of mTOR and autophagy are revealing how we can delay the onset of age-related diseases and achieve significant increases in life span and health span.

When rapamycin crosses a cellular membrane and enters a cell, it binds with an enzyme that was named mTOR, which stands for the mechanistic target of rapamycin (mTOR). mTOR is a key regulator of cellular metabolism that has stimulated a great deal of scientific interest.

Now, 25 years after its discovery, over 12,000 papers have been published on mTOR. When nutrients are available to a cell, mTOR sends cellular signals that activate cellular metabolism, telling the cell to use the available nutrients to build new proteins, new enzymes, and other cellular components. mTOR activates cellular anabolic (building) processes of growth and proliferation.

Counterbalancing mTOR is the cellular process known as autophagy. In 2016, Japanese scientist Yoshinori Ohsumi was awarded the Nobel Prize in physiology and medicine for discovering the mechanism of autophagy. PubMed now contains over 30,000 citations with the term autophagy in the title, which gives an indication of the scientific interest in this topic.

Autophagy has been referred to as the cellular housekeeping process or cellular trash removal. Over time, various cellular components become damaged, break down, and become dysfunctional. If these waste products continue to accumulate, cellular functions would decline, and the cell(s) would eventually die. When autophagy is activated, damaged and dysfunctional cellular components are broken down for reuse and recycling or for removal. Autophagy can also be thought of as cellular detoxification.

Animals get many of the same age-related diseases that humans get. Rapamycin gained prominence as a life extension drug based on its ability to treat a variety of age-related diseases and increase the lifespan in numerous species of animals. However, human trials were lacking because ethical issues, costs, and time constraints, make it virtually impossible to conduct life extension trials in humans.

Breakthrough: Rapamycin's Use in Humans

Twas the night before Christmas....on Dec. 24, 2014, a groundbreaking study titled mTOR inhibition improves immune function in the elderly was published that ushered in the era of rapamycin use in humans. The study was conducted by Joan Mannick, MD, who was a senior scientist at Novartis. In addition to being a human clinical trial, Mannick's study is important because it sheds light on WHY and HOW rapamycin can be used safely and effectively in humans to slow down the onset of age-related diseases and increase lifespan and healthspan.

In this trial, elderly adults were treated with RAD001, which is a synthetic version of rapamycin (a rapalog) whose effects are virtually the same as rapamycin. Dr. Mannick's wanted to evaluate the effects of mTOR inhibition on human aging-related conditions and she chose the immune system, which normally declines with age, as the target for her study.

In this 6-week placebo-controlled trial, 218 volunteers who were 65 years of age or older were divided into four groups. The doses administered were 0.5 mg daily, 5.0 mg once weekly, 20 mg once weekly, or placebo. Following 6-weeks of therapy, there was a 2-week drug-free interval followed by administration of the seasonal flu vaccine.

The immune system of the elderly adults who received a 5 mg dose of RAD001 once weekly exhibited a 20% enhanced response to the influenza vaccine with virtually no side effects. The results of this clinical trial suggested that the ability of rapamycin or similar rapalogs to enhance immune function in elderly adults might be able to delay the onset of age-related diseases in humans.

Joan Mannick's study helps us understand that rapamycin's initial classification as an immunosuppressant drug was incorrect. Rapamycin is not an immunosuppressant, it is an immunomodulator.

The mTOR/Autophagy Ratio

Life....it's all about balance. This is especially true regarding the mTOR/autophagy ratio. Extreme suppression of mTOR (hypo-functioning) results in suppression of the immune system. This is what happens when rapamycin is administered daily to prevent organ rejection following organ transplant surgeries.

When mTOR is hyper-functioning, the immune system gets exhausted, which also results in immunosuppression. I believe most people alive today suffer from an under-functioning immune system, which is due to the continual over-activation of mTOR. I call this condition mTOR Syndrome.

Dysregulated mTOR/Autophagy Ratio

The majority of Americans are not well. We are literally experiencing an epidemic of epidemics. We have an epidemic of cancer, heart disease, diabetes, obesity, osteoporosis, Alzheimer's disease, ADD/ADHD, autism, opioid addiction, to name a few. The over-expression of mTOR (mTOR Syndrome) is increasingly being recognized as a fundamental mechanism that is present in many of our common diseases such as cancer, diabetes, cardiovascular disease, and Alzheimer's disease.

I believe most people living today are suffering to some degree from mTOR Syndrome. Understanding why the mTOR/autophagy ratio has become so universally unbalanced will help explain our epidemic of chronic degenerative diseases, and also explain why rapamycin appears to be effective (in animal studies) in the treatment of such a wide range of diseases.

Within the past 300 years, humans have managed to get the mTOR/autophagy ratio severely out of balance. Two categories of technological advancement have played a large role in the development of mTOR Syndrome.

The first technological advancement was the invention and development of refrigeration, which greatly improved the ability to store and preserve foods and make them easily available. Artificial refrigeration began in the mid-1750s. The first home refrigerators were invented in 1913. Fast forward to today and the refrigerator has become the most popular home appliance. According to government data, nearly 100% of American households have a refrigerator and approximately 25% of homes have two (or more) fridges and/or freezers.

The second technological advancement that played a major role in dysregulating the mTOR/autophagy balance was the rapid development of the industries of food processing and packaging. The rapid development of refrigeration, food processing, and the widespread production and distribution of conven.

About the Author

1 Harrison DE, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. 2 McCay CM, et al. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition. 1989, 5: 155-71. 3 Lashinger LM, et al. Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. Cancer Prev Res. July 2011;4:1041-101. 4 Ye Lan, et al. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front Genet 2012 Sep 11;3:177. 5 Mondesire WH, et al. Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells.Clinical Cancer Research. 2004 Oct 15;10(20:7031-42. 6 Bjedov I, et al. Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster. Cell Metab. 2010 Jan 6;11(1):35-46. 7 ClinicalTrials.gov. Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study. https: //clinicaltrials.gov/ct2/show/NCT04488601 8 Miller RA, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. The journals of gerontology Series A, Biological sciences and medical sciences. 2011;66(2):191-201. 9 Miller RA, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13(3):468-477. 10 Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Aging (Albany NY). 2019 Oct 15(11(19):8048-8067. 11 Blagosklonny MV An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Discov Today. 2007 Mar; 12(5-6):218-24. 12 Mannick JB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179. 13 Chang GR, et al. Long-term Administration of Rapamycin Reduces Adiposity, but Impairs Glucose Tolerance in High-Fat Diet-fed KK/HIJ Mice. Basic Clin Pharmacol Toxicol. 2009 Sept;105(3):188-98. 14 Halford B. Rapamycin's secrets unearthed. Chemical & engineering News. July 18, 2016'94(29). 15 Gerber K. Rapamycin's Resurrection: A New Way to Target the Cancer Cell Cycle. J Natl Ca Inst. 17 Oct 2001;93(20):1517-1519.16 Sudarsanam S and Johnson DE. Functional consequences of mTOR inhibition.Curr Opin Drug Discov Devel. 2010 Jan;13(1):31-40. 17 Masoro EJ. Dietary restriction-induced life extension: a broadly based biological phenomenon. Biogerontology. 2006;7(3):153-155 18 Everitt AV and Le Couteur DG. Life extension by calorie restriction in humans. Ann N Y Acad Sci. 2007 Oct;1114:428-33. 19 Brown EJ, et al. A mammalian protein targeted by G1-arresting rapamycinreceptor complex". Nature. June 1994;369 (6483): 756-8. 20 Sabatini DM, et al. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. July 1994;78 (1): 35-43. 21 Sabers CJ, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. Jan 1995;270(2):815-22. 22 Gomes LR, et al. Autophagy Roles in the Modulation of DNA Repair Pathways.Int J Mol Sci. 2017 Nov 7;18(11):2351. 23 Vishniakova KS, et al. Possible role of autophagy activation in the stimulation of regeneration. Mol Biol (Mosk). Sept0Oct 2013;47(5):796-802. 24 Khalil H, et al. The Mechanical Autophagy as Part of Cellular Immunity; Facts and Features in Treating the Medical Disorders. Immunol Invest. 2020 Sep 29;1-24. 25 Press Release: 2016 Nobel Prize in Physiology or Medicine. https: //www. nobelprize.org/prizes/medicine/2016/press-release/ 26 Stroikin Y, et al. Testing the "garbage" accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy. Biogerontology. 2005 Jan;6:39-47. 27 Glick D, at al. Autophagy: cellular and molecular mechanisms. J Pathol. 2010 May;221(1):3-12. 28 Fang Y, et al. Signaling pathways and mechanisms of hypoxia-induced autophagy in the animal cells. Cell Biol Int. 2015 Aug;39(8):891-8. 29 Scherz-Shouval R, et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007 Apr 4;26(7):1749-60. 30 Deleyto-Seladas N and Efeyan A. The mTOR-Autophagy Axis and the Control of Metabolism. Front Cell Dev Biol. 2021 Jul 1;9:655731. 31 Kim YC and Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. Jan 2, 2015;125(1):25-32. 32 Cota D, et. al. Hypothalamic mTOR Signaling Regulates Food Intake. Science. 2006 May 12;312(5775):927-930. 33 Vijayakumar K. Autophagy: An evolutionarily conserved process in the maintenance of stem cells and aging. Cell Biochemistry and Function. 2019 July19;37(6). https: //onlinelibrary.wiley.com/doi/10.1002/cbf.3427 34 Hall MN. mTOR-what does it do? Transplantation Proceedings. 2008 Dec;40(10 Suppl): S5-S8.35 Kourtis N and Tavernarakis N. Autophagy and cell death in model organisms Cell Death & Differentiation. 2009 Jan;16(1):21-30. 36 Swindell WR. Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan. Ageing Res Rev. 2012 Apr;11(2):254-270. 37 Masoro EJ. Dietary restriction-induced life extension: a broadly based biological phenomenon. Biogerontology. 2006;7(3):153-155. 38 Bodkin NL, et al. Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. J Gerontol A Biol Sci Med Sci. 2003;58(3):212-219. 39 Anton SD, et al. Caloric Restriction to Moderate Senescence: Mechanisms and Clinical Utility. Curr Transl Geriatr Exp Gerontol Rep. 2013 Dec 13;2(4):239-246. 40 Johnson JB, et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med. 2007;42:665-674. 41 Eaton SB, et al. Stone agers in the fast lane: chronic degenerative diseases in evolutionary prespective. Am J Med. 1988 Apr;84(4):739-49. 42 Rapamycin and Rapalogs. Lamming D. Preprints 2021, 2021020491 (doi:10.20944/preprints202102.0491.v1). 43 Kennedy BK and Lamming DW. The mechanistic Target of Rapamycin: The grand conductor of metabolism and aging. Cell Metab. 2016 Jun 14;23(6):990- 1003. 44 Beauchamp EM and Platanias LC. The evolution of the TOR pathway and its role in cancer. Oncogene. 2013;32:3923-3932. 45 Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol. 2010 Apr;7(4):209-19. 46 Law BK. Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol. 20015 Oct;56(1):47-60. 47 Sherston SN, et al. Predictors of Cancer Risk in the Long-Germ Solid-Organ Transplant Recipient. Transplantation. 2014 Mar 27;97(6):605-611. 48 United Network for Organ Sharing. 2021 Jan 11. https: //unos.org/news/ deceased-organ-donation-and-transplant-annual-trend-continues-2020/ 49 Tessari G and Girolomoni G. Nonmelanoma Skin Cancer in Solid Organ Transplant Recipients: Update on Epidemiology, Risk Factors, and Management. Dermatologic Surgery. Oct 2012;38(10):1622-1630. 50 Alter M, et al. Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients. J Dtsch Dermatol Ges. 2014 Jun;12(6):480-8. 51 iData Research. https: //idataresearch.com/stents-implanted-per-year-in-theu-s/52 Chisari A, et al. The Ultimaster Biodegradable-Polymer Sirolimus_Eluting Stent: An Updated Review of Clinical Evidence. Int J Mil Sci. 2016;17(9):1490. 53 Zhu F. Neuroprotective effect of rapamycin against Parkinson's disease in mice. Journal of Zhejiang University. 2018 May 25;47(5):465-472. 54 Spillman 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. 2010 Apr 1;5(4): e9979. 55 Bagherpour B, et al. Promising effect of rapamycin on multiple sclerosis. Mult Scler Relat Disord. 2018 Nov;26:40-45. 56 Wen HY, et al. Low-Dose Sirolimus Immunoregulation Therapy in Patients with Active Rheumatoid Arthritis: A 24-Week Follow-up of the Randomized, Open-Label, Parallel-controlled Trial. J Immunol Res. 2019 Nov 3;2019:7684352. 57 Piranavan P and Peri A. Improvement of renal and non-renal SLE outcome measures on sirolimus therapy - A 21-year follow-up study of 73 patients. Clin Immunol. 2021 Aug;229:108781. 58 Callahan EA editor. Current Status and Response to the Global Obesity Pandemic: Proceedings of a workshop. 2019 Jun 25. https: //pubmed.ncbi.nlm.nih.gov/31334935/ 59 Fryar CD, et al., Prevalence of Overweight, Obesity, and Severe Obesity Among Adults Aged 20 and Over: United States, 1960-1962 Through 2017-2018. https: //www.cdc.gov/nchs/data/hestat/obesity-adult-17-18/obesity-adult.htm 60 Hwangbo DS, et al. Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms. Nutrients 2020;12(4):1194. 61 Roth LS and Polotsky AJ. Can we live longer by eating less: A review of caloric restriction and longevity. Maturitas. 2012 Apr;71(4):315-319. 62 Most J, et al. Calorie restriction in humans: an update. Ageing Res Rev. 2017 Oct;39:36-45. 63 Stunkard, A. J., McLaren-Hume, M. (1959) The results of treatment for obesity. Arch Intern Med 103: 79-85. 64 Deblon N, et al. Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats. Br J Pharmacol. 2012 Aapr;165(7):2325-2340. 65 Rovira J, et al. Effect of mTOR inhibitor on body weight: from an experimental rat model to human transplant patients. Transpl Int. 2008 Oct;21(10):992-8. 66 Scarpace PJ, et al. Rapamycin Normalizes Serum Leptin by Alleviating Obesity and Reducing Leptin Synthesis in Aged Rats. J Gerontol A Biol Sci Med Sci. 2016 Jul;71(7):891-9. 67 Toutouzas K, et al. Sirolimus-eluting stents: a review of experimental and clinical findings. Z Karkiol. 2002;91 Suppl 3:49-57. 68 Boada C, et al. Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation. Circulation Research. 2020;126:25-37.69 Nhuyen QD, et al. Noninfectious Uveitis: Evolution through Preclinical and Clinical Studies. Ophthalmology. 2018 Dec;125(12):1984-19+93. 70 Shen G, et al. Mammalian target of rapamycin as a therapeutic target in osteoporosis.J Cell Physiol. 2018 May;233(5):3929-3944. 71 Yin ZY, et al. Rapamycin facilitates fracture healing through inducing cell autophagy and suppressing cell apoptosis in bone tissues. Eur Med Pharmacol Sci. 2017 Nov;21(21):4989-4998. 72 Yang GE, et al. Rapamycin-induced autophagy activity promotes fracture healing in rats. Eur Ther Med. 2015 Oct;10(4):1327-1333. 73 Martin SA, et al. Rapamycin impairs bone accrual nin young adult mice independent of Nrf2. Exp Gerontol. 2021 Aug 10;111516. 74 Hussein O, et al. Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases. Cancer Letters. 2012 Jan;414(2):176-84. 75 Gambacurta A, et al. Human osteogenic differentiation in Space: proteomic and epigenetic clues to better understand osteoporosis. Sci Rep. 2019 Jun 6;9(1):8343. 76 Bari M, et al. The SERiSM project: preliminary data on human stem cell reprogramming in microgravity. Frontiers in Physiology. Jan 2018. https: //www. frontiersin.org/10.3389%2fconf.fphys.2018.26.00038/event_abstract 77 Luo D, et al. Rapamycin reduces severity of senile osteoporosis by activating osteocyte Autophagy. Osteoporosis International. 2016;27:1093-1101. 78 Wang L, et al. Male rodent model of age-related bone loss in men. Bone. 2001;29(2):141-148. 79 Kuo D, et al. Rapamycin reduces severity of senile osteoporosis by activating osteocyte autophagy. Osteoporosis International. 2016;27;1093-1101. 80 Li XN, et al. Rapamycin activates autophagy by inhibition mTOR pathway to alleviate early osteoporosis in rats with skeletal fluorosis. Chinese Journal of Industrial Hygiene and Occupational Diseases. 2021 May 20;39(5):321-327. 81 Altschuler RA, et al. Tapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice. Front Cell Neurosci. 2021 Apr 7;15:658972. 82 Hosoya M, et al. Estimating the concentration of therapeutic range using disease-specific iPS cells: Low-dose rapamycin therapy for Pendred syndrome. Regen Ther. 2018 Dec 17;10:54-63. 83 Dhadse P, et al. The link between periodontal disease and cardiovascular disease: How far we have come in the last two decades? J Indian Soc Periodotol. 2010 Jul-Sep;14(3):148-154. 84 Beydoun MA, et al. Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey. J Alzheimer's Dis. 2020;75(1):157-172.85 An JY, et al. Rapamycin rejuvenates oral health in aging mice. Elife.2020 Apr 28;9: e54318 86 Kolosova NG, et al. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats. Am J Pathol. 2012 Aug;181(2):472-7. 87 Niu Z, et al. Protective effect of rapamycin in models of retinal degeneration. Exp Eye Res. 2021 Sep;210:108700. 88 Su W, et al. Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model. PLoS One. 2014 Jun 12;9(6): e99719. 89 Harder JM, et al. Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin. Proc Natl Acad Sci USA. 2020 Dec 29;117(52):33619-33627. 90 Li Q, et al. Current understanding of ovarian aging. Sch China Life Sci. 2012 Aug;55(8):659-69. 91 Moline-Garcia L, et al. The delay of motherhood: Reasons, determinants, time used to achieve pregnancy, and maternal anxiety level. PLOS ONE. 2019 Dec 30;14(2): e0227063. 92 Dou X, et al. Short-term rapamycin treatment increases ovarian lifespan in your and middle-aged mice. Aging Cell. 2017 May 22. 93 Luo L, et al. Rapamycin prolongs female reproductive lifespan. Cell Cycle. 2013 Nov 1;12(21):3353-4. 94 DeKlotz CMC, et al. Dramatic improvement of facial angiofibromas in tuberous sclerosis with topical rapamycin: optimizing a treatment protocol. Arch Dermatil. 2011 Sep;147(9):1116-7. 95 Wheless JW, et al. A Novel Topical Rapamycin Cream for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex. J Child Neurology. 2013 Jul;28(7):933-6. 96 Burger C, et al. Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice. Acta Derm Venereol. 2017 Oct 2;97(9):1087-1094. 97 Ekici Y, et al. Effect of rapamycin on wound healing: an experimental study. Transplant Proc. 2007 May;39(4):1201-3. 98 Costa-Mattioli M, Monteggia LM. mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 2013; 16: 1537-1543. 99 Ricciardi S, et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet 2011; 20: 1182-1196. 100 Oddo S. The role of mTOR signaling in Alzheimer disease. Front Biosci 2012; 4: 941-952. 101 Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., et al. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PLoS One 5: e9979.102 Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY). 2019 Oct 15;11(19):8048-8067. 103 Bitto A, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016; Aug 23;5: e16351. 104 Johnson SC, et al. Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Front Genet. 2015; 6:247. 105 Taylor DH, et al. Benefits of smoking cessation for longevity. Am J Public Health. 2002; 92:990-96. 106 Tang H, et al. Rapamycin protects aging muscle. Aging (Albany NY). 2019 Aug 31;11(16):5868-5870. 107 Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006; 5:2087-102. 108 Wang H, et al. Mammalian target of rapamycin inhibitor RAD001 sensitizes endometrial cancer cells into paclitaxel-induced apoptosis via the induction of autophagy. Oncol Lett. 2016 Dec. 12(6):5029-5035. 109 Coppock JF, et al. mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC. Oncotarget. 2016 Apr 26;7(17):24228-41. 110 Perk J. Non-communicable diseases, a growing threat to global health. European Society of Cardiology. 2017 Aug 30;15(14). 111 Shih YC and Hurria A. Preparing for an epidemic: cancer care in an aging population. Am Soc Clin Oncol Edu Book. 2014:133-7. 112 Ounpuu S, et al. The impending global epidemic of cardiovascular diseases. Eur Heart J. 2000 Jun;21(11):880-803. 113 Malmborg P and Hildebrand H. The emerging global epidemic of pediatric inflammatory bowel disease-causes and consequences. J Intern Med. 2016 Mar;279(3):241-58. 114 Saklayen MG. The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep. 2018 Feb 26;20(2):12. 115 Kim R. et al. Understanding the obesity epidemic. BMJ. 2019 Jul 3;366:14409. 116 New M. Arthritis: an impending public health epidemic. J Okla State Med Assoc. 2001 Feb;94(2):63-64. 117 Lee TS and Krishnan KR. Alzheimer's disease-the inexorable epidemic. Ann Acad Med Singapore. 2019 Jul;39(7):505-2. 118 Graf WE. Et al. The autism "epidemic" Ethical, legal, and social issues in a developmental spectrum disorder. Neurology. 2017 Apr 4;88(14):1371-1380. 119 Lardizabal A. Is financial gain to blame for the growing ADHD epidemic? J Child Adolesc Psychiatr Nurs. 2012 Aug;25(3):164. 120 NAFLD-NASH: An Under-Recognized Epidemic. Curr Vasc Pharmacol. 2018;16(3):209-213.121 Tucci V and Moukaddam N. We are the hollow men: The worldwide epidemic of mental illness, psychiatric and behavioral emergencies, and its impact on patients and providers. J Emerg Trauma Shock. 2017 Jan-Mar;10(1):4-6. 122 Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY). 2019 Oct 15;11(19):8048-8067. 123 Lins Vieira RF. Et al. Exercise activates AMPK signaling: Impact on glucose uptake in the skeletal muscle in aging. J Rehab Therapy. Aug 4, 2020;2(2):48-53. 124 Ashrafizadeh M. et al. Autophagy regulation using luteolin: new insight into its anti-tumor activity. Cancer Cell Int. 2020 Nov 4;20(1):537. 125 Theoharides TC, et al. Brain "fog" inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci. 2 July 2015;9:225. 126 Makhov P, et al. Piperlongumine promotes autophagy via inhibition of Akt/ mTOR signaling and mediates cancer cell death. British Journal of Cancer. Jan 16, 2014;110:899-907. 127 Aggarwal BB and Harikumar KB. Int J Biochem & Cell Biology. Jan 2009;41(1):40-59. 128 Guo S, et al. Curcumin activates autophagy and attenuates oxidative damage in EA.hy926 cells via the Akt/mTOR pathway. Mol Med Rep. 2016 Mar13(3):2187-93. 129 Shen L, et al. Curcumin and aging. Biofactors. Jan-Feb 2013;39(1):133-40. 130 Amamd P, et al. Bioavailability of Curcumin: Problems and Promises. Mol. Pharmaceutics. 14 Nov 2007;4, 6, 807-818. 131 Kumar D, et al. Enhanced bioavailability and relative distribution of free (unconjugated) curcuminoids following the oral administration of a foodgrade formulation with fenugreek dietary fibre: A randomized double-blind crossover study. J Functional Foods. 2016 Apr;22:578-587. 132 Lee HS. Gynostemma Pentaphyllum Extract Ameliorates High-Fat Diet- Induced Obesity in C57BL/6N Mice by Upregulating SIRT1. Nutrients. 2019 Oct 15;11(10):2475. 133 Rao A, et al. The effect of an orally-dosed Gynostemia pentaphyllum extract (ActivAMP(R)) on body composition in overweight, adult men and women: A double-blind, randomized, placebo-controlled study. J Hum Nutr Diet. 2021 Jul 29. https: //pubmed.ncbi.nlm.nih.gov/34323337/ 134 Rahmani AH, et al. Implications of Green Tea and Its Constituents in the Prevention of Cancer via Modulation of Cell Signalling Pathway. BioMed Res Int. 2015 Apr 21;2015:925640. 135 Wiernsperger NF and Bailey CJ. The Antihypertensive Effect of Metformin. Drugs. 1999;58 Suppl 1:31-9; discussion 75-82. 136 Wang YW, et al. Metformin: a review of its potential indications. Drug Des Devel Ther. 2017;11:2421-2429.137 Cork CK, et al. Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling. Fron Endocrinol (Lausanne). 2018;9:522. 138 Yang X, et al. Metformin, beyond an insulin sensitizer, targeting heart and pancreatic beta cells. Biochim Biophys Acta Mol Basis Dis. 2017 Sug;1863(8):1984-1990. 139 Schneider MB, et al. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 2001 Apr; 120(5):1263-70. 140 Libby G, et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009 Sep;32(9):1620-5. 141 National Institutes of Health (NIH): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD): Overweight & Obesity Statistics. https: //www.niddk.nih.gov/health-information/health-statistics/overweightobesity 142 Stevanovic D, et al. Intracerebroventricular administration of metformin inhibits ghrelin-induced hypothalamic AMP-kinase signaling and food intake. Neuroendocrinology. 2012; 96: 24-31. 143 Adeyemo MA, et al. Effects of metformin on energy intake and satiety in obese children. Diabetes Obes Metab. 2014; 17: 363-370. 144 Chen C, et al. mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells. Sci Signal. 2009;2(98): ra75. 145 Chen C, et al. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009 Nov 24;2(98): ra75. 146 Urfer SR, et al. A randomized controlled trial to establish the effects of shortterm rapamycin treatment in 24 middle-aged companion dogs. GeroScience. 2017 Apr;39(2):117-127. 147 Dai DF, et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell. 2014 Jun;13(3):529-39.

Product Details
ISBN: 9781607660156
ISBN-10: 1607660156
Publisher: Hunter Lewis Foundation
Publication Date: May 1st, 2022
Pages: 135
Language: English

We recommend