Ce diaporama a bien été signalé.
Nous utilisons votre profil LinkedIn et vos données d’activité pour vous proposer des publicités personnalisées et pertinentes. Vous pouvez changer vos préférences de publicités à tout moment.

RAADfest 2019 Bill Faloon's Senolytics Slides

3 860 vues

Publié le

Bill Faloon presents a research update on senolytic research.

Publié dans : Santé & Médecine
  • Identifiez-vous pour voir les commentaires

  • Soyez le premier à aimer ceci

RAADfest 2019 Bill Faloon's Senolytics Slides

  1. 1. Senolytic Update October 3rd 2019
  2. 2. Senolytics are compounds that selectively destroy senescent cells.
  3. 3. Senescent cells accumulate with normal aging and: Removing Senescent Cells Confers Healthy Longevity
  4. 4. Normal Age Mouse Senolytic Treated Mouse Naturally occurring p16Ink4a-positive cells shorten healthy lifespan.” Update published in: Nature. 2016 Feb 11; 530(7589): 184–189.
  5. 5. Senolytics Extend Healthy Lifespan  Improve frailty symptoms (gait, grip strength)  Improve kidney/liver pathologic age scores  Improve cardiac/arterial function  Reduce tremors and urinary incontinence  Decrease osteoporosis  Increase exercise endurance  Enhance coat color appearance  Extend healthy lifespan Dasatinib + Quercetin Does anyone NOT want these benefits? Preclinical (rodent) model shows quercetin + dasatinib Zhu, Yi, Tamara Tchkonia, Tamar Pirtskhalava, Adam C. Gower, Husheng Ding, Nino Giorgadze, Allyson K. Palmer et al. "The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs." Aging cell 14, no. 4 (2015): 644-658.
  6. 6. Anti-Cancer Properties of Senolytics May. 17, 2019 https://science.sciencemag.org/content/364/6441/636.full “Indeed, elimination of senescent cells with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.”
  7. 7. Senescentcellssecretetoxicsenescence associatedsecretoryphenotype(SASP) May. 17, 2019 https://science.sciencemag.org/content/364/6441/636.full “Can stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting development of late-life cancers.”
  8. 8. I. Damaging extracellular matrix II. Inducing fibrosis III. Inhibiting stem cell function IV. Fueling inflammation Senescentcellssecretetoxicsenescence associatedsecretoryphenotype(SASP) May. 17, 2019 https://science.sciencemag.org/content/364/6441/636.full SASP accelerates aging by:
  9. 9. Example of Senolytic Age Delay Normal aged mouse has characteristic bent-spine, cataracts, and loss of coat fur (hair). https://www.cnbc.com/2018/08/29/-jeff-bezos-is-backing-this-scientist-who-is-working-on-a-cure-for-aging.html Same aged mouse from senolytic-treated group appears outwardly younger and healthy. Bent spine Cataract Same age mouse looks much youngerHair loss https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101/ Untreated Senolytic Treated Starting at Mid-Age
  10. 10. Improved organ function when senescent cells are removed https://www.cnbc.com/2018/08/29/-jeff-bezos-is-backing-this-scientist-who-is-working-on-a-cure-for-aging.html Bent spine Cataract Same age mouse looks much youngerHair loss https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101/ Normal Age Same Age / Senolytic Treated  Improved kidney function.  Hearts more resilient to stress.  Extended lifespans.
  11. 11. Lifespan Increase in Senolytic-Treated Mice Median lifespans increased 24% to 27% https://www.cnbc.com/2018/08/29/-jeff-bezos-is-backing-this-scientist-who-is-working-on-a-cure-for-aging.html Bent spine Cataract Same age mouse looks much youngerHair loss https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101/ Normal Age Same Age / Senolytic Treated Internal measures show improved organ function in senolytic-treated group This finding may indicate that humans scheduled to die at age 80 may live to age 100 in relatively good health…using this one intervention
  12. 12. “We are encouraged by the safety and tolerability observed to date in this first study of a senolytic drug in patients with osteoarthritis. It is that experience in patients that gives us the confidence to initiate Part B at the highest evaluated dose.” UNITY Biotechnology, Inc. is a company developing therapeutics to extend healthspan by slowing, halting or reversing diseases of aging using a patented senolytic compound. EXPANDS ONGOING PHASE 1 STUDY TO FURTHER EVALUATE SENESCENT CELL FACTORS IN OSTEOARTHRITIS http://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-expands-ongoing-ubx0101-phase-1-study “A Senolytic Drug Company” Jan. 22, 2019
  13. 13. SEPTEMBER 17, 2018 Scientific Discovery and the Future of Medicine Journal of the American Medical Association “Interventions aimed at eliminating those senescent cells, commonly called senolytic, have also been shown to improve health and extend life in various mouse disease models. “If senolytics are shown to be safe and effective in humans, they could transform care of older adults and patients with multiple chronic diseases.” JAMA. Published online September 17, 2018. doi:10.1001/jama.2018.12440 Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies “…many human pathologic conditions are associated with the presence of senescent cells.”
  14. 14. July 9, 2018 Magazine “It’slooking like veryoldmice are able to substantially improve their health span, reduce or delay age-related diseases and increase their survival.” They calculated that if only one in 7,000 to 15,000 cells is senescent, then age-related problems in physical function started to appear in the mice. Like a contagion, senescent cells seem to pass on their accelerated aging abilities to healthy cells by releasing a number of factors that can cause tissues like muscle to deteriorate. Mice given senescent cells and the senolytic compounds lived 36% longer than animals with senescent cell transplants who were not given the drugs. How Scientists Are Testing Cancer Drugs to Slow Down Aging https://time.com/5333752/aging-drugs/
  15. 15. This drug cocktail reduced signs of age-related diseases and extended life in mice and human cells Senolytic Delay May = Death “Group led by Mayo Clinic anti-aging researcher James Kirkland not only offers a clear look at the power of senescent cells to drive the aging process, but also a pharmaceutical cocktail that, in mice at least, can slow and even reverse it. Compared to mice who aged normally, those who started getting the dasatinib-quercetin cocktail at an age equivalent to 75 to 90 years in humans ended up living roughly 36% longer, and with better physical function. In human cells in a test tube and in mice bearing human senescent cells, the dasatinib-quercetin cocktail showed equally promising results, targeting senescent cells while leaving other cells intact. Aging…is beginning to look more and more like a disease — and a treatable one at that. ScientistsAre Testing CancerDrugstoSlowDownAging July 10, 2019
  16. 16. Journal of the American Medical Association “Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies.” JAMA Online-Sept 17 2018 “…patients should be advised not to self-medicate with senolytic agents or other drugs that target fundamental aging processes in the expectation that conditions alleviated in mice will be alleviated in people. Senolytics represent a new potential treatment approach, and the adverse effects of these therapies remain to be elucidated.” Experts Tell Us to Wait… Scientific Discovery and the Future of Medicine
  17. 17. First Published Human Senolytic Clinical Trial Jan 7, 2019THE LANCET
  18. 18. Drug to clear 'zombie cells' from body could be first anti-aging treatment after ‘impressive’ human trial https://www.telegraph.co.uk/science/2019/01/08/drug-clear-zombie-cells-body-could-first-anti-ageing-treatment/ Jan. 8, 2019 “A drug to fight aging may finally be on the horizon after the first trial in humans showed ‘impressive’ results.” “The treatment clears out dead cells even when the immune system no longer can.”
  19. 19. The treatment protocol consisted of dasatinib and quercetin https://www.telegraph.co.uk/science/2019/01/08/drug-clear-zombie-cells-body-could-first-anti-ageing-treatment/ Jan. 8, 2019 “Previously animal studies have shown that removing these cells reverses the aging process, extends lifespan, and restores lost youth” “Now for the first time scientists in the US have shown improvements in humans using a drug that sweeps away the defunct cells.”
  20. 20. Dr. James Kirkland - Mayo Clinic https://newsnetwork.mayoclinic.org/discussion/removal-of- zombie-cells-alleviates-causes-of-diabetes-in-obese-mice/ Jan. 8, 2019 “This is like a glimmer that it might actually work. The results were impressive. All 14 (humans) got better in their functional ability.” https://www.telegraph.co.uk/science/2019/01/08/drug- clear-zombie-cells-body-could-first-anti-ageing-treatment/
  21. 21.  Reduced glucose levels  Improved insulin sensitivity  Decline in inflammatory factors  Return to normal fat cell function  Improved kidney & heart function Removal of 'zombie cells' alleviates causes of diabetes in obese mice Mar 25, 2019 Removal of senescent cells: https://www.sciencedaily.com/releases/2019/03/190325120339.htm
  22. 22. Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults Diabetes No Data < 14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% > 26.0% No Data < 4.5% 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% > 9.0% Age-Adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults CDC’s Division of Diabetes Translation. United States Diabetes Surveillance System available at http://www.cdc.gov/diabetes/data 1994 2000 2015 Diabetes1994 20152000 Obesity
  23. 23. “National Institute on Aging Intramural Research Program added substantial proof that senolytics, the golden child of anti-aging drugs, rescue memory loss in Alzheimer’s disease, at least in mice genetically engineered to accumulate amyloid clumps in their brains.” “Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model” Apr. 1, 2019 Senolytics Effective in Mouse Model of Alzheimer’s https://www.nature.com/articles/s41593-019-0372-9
  24. 24. “The treated mice also had fewer senescent cells in their hippocampus, the brain’s main memory center, and navigated complex water mazes better than their peers.” Apr. 15, 2019 Dasatinib + Quercetin Mitigates Alzheimer’s and Improves Cognitive Performance https://singularityhub.com/2019/04/15/senolytics-show-promise-against-alzheimers-in-mice/ “The team squirted the drug cocktail (dasatinib and quercetin) into their Alzheimer’s mice once a week for 11 weeks.” “Positive results came fast: the mice’s beta-amyloid levels dropped within three months.”
  25. 25. Apr. 15, 2019Senolytics Restore Memory “Our findings pave the way for future preclinical and clinical studies that will test the hypothesis that senolytic therapies can … preserve brain function in [Alzheimer’s] and other age-related neurodegenerative disorders…” https://singularityhub.com/2019/04/15/senolytics-show-promise-against-alzheimers-in-mice/ “In a series of memory tests, the treated mice regained their ability to learn and memorize complex mazes.” Conclusions from the study
  26. 26. 8 Million Americans Suffer Chronic Heart Failure Clinical trial on existing senolytic compounds urgently needed! Senescence involving cardiomyocytes (i.e. cardiac muscle cells) appears to be associated with age-linked fibrosis and hypertrophy of the heart. Pharmacologic and genetic removal of p16-positive (senescent) cells in mice appears to ameliorate (or improve) the level of age- induced fibrosis and hypertrophy in senescent cardiac muscle cells, and may support regeneration of cardiomyocytes… What we learned from the first 2019 published study:
  27. 27. “Declining Risk of Sudden Death in Heart Failure." New England Journal of Medicine; 2017;377(1):41-51. Clinical trials spanning 1995 to 2014 show: 44% decline of sudden death in heart failure patients Sharp Decline in Heart Failure Death Rates Leading cause of age-related death markedly reduced in just 19 years!
  28. 28. Heart failure is more common in some areas of the United States than in others. This map shows the rate of death from heart failure by county during 2014–2016. Deaths from Heart Failure Vary by Geography
  29. 29. https://www.hindawi.com/journals/sci/2018/8283648/ Today’s Dilemma https://www.ncbi.nlm.nih.gov/pubmed/29020403 No treatment fully reverses damage or completely restores cardiac function in heart failure patients. Patients progress towards complete heart failure. Progenitor cell restoration and renewal is a potential solution.
  30. 30. “Aged‐senescent cells contribute to impaired heart regeneration.” Aging Cell; June 2019 Senescent Cells Damage Aging Hearts “Aging leads to increased cellular senescence and is associated with decreased potency of tissue‐specific stem/progenitor cells.” “In aged subjects (>70 years old), over half of cardiac progenitor cells are senescent…” “Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.”
  31. 31. https://onlinelibrary.wiley.com/toc/14749726/2019/18/3 Senescent Cells Damage Everything Aged‐senescent cells contribute to impaired heart regeneration Targeting senescent cells alleviates obesity‐induced metabolic dysfunction The eliminationof p16‐expressing cellsin oldmice, using the INK‐ATTACtransgene, increases bone mass indicatingthat senescent cells contribute to skeletalaging. Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction Systemic clearance of p16INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration An early‐senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro‐inflammatory program This is the featured research from just ONE JOURNAL ISSUE
  32. 32. Stem Cells Bone Marrow Progenitor Cells Functional Cells Healthy Cardiac Output Where Do Cardiac Progenitor Cells Come From?
  33. 33. “Aged‐senescent cells contribute to impaired heart regeneration.” Aging Cell; June 2019 Senescent Cells Thwart Progenitor Cell Regeneration When senolytics ( ) were administered in vivo to elderly mice, cardiac progenitor cells reactivated and began remodeling the aged hearts. Senescent progenitor cardiac cells are unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into infarcted mouse heart.
  34. 34. “Senescent cells – also known as zombie cells – form in the heart during aging and lead to heart failure.” “Newcastle scientists, in collaboration with researchers in the Mayo Clinic… not only discovered how this process takes place in the heart but also how it can be reversed or treated.” Newcastle University scientists are killing zombie cells to reverse age-related damage in the heart Feb.8,2019British Heart Foundation https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2019/february/newcastle-university-scientists-are-killing-zombie-cells-to-reverse-age-related-damage-in-the-heart
  35. 35. “Scientists believe it may be possible to reverse the heart damage caused by aging” Rhys Anderson et al. Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence, The EMBO Journal (2019). DOI: 10.15252/embj.2018100492 Feb. 11, 2019 "We saw that removing senescent cardiomyocytes from the hearts of aged mice, both genetically and using drugs, was able to restore cardiac health – essentially removing the damage caused by aging. This data provides critical support for the potential of using medicines to kill zombie cells. If this is validated through clinical trials it would provide us with a new way of treating cardiac diseases."
  36. 36. Stem Cells Bone Marrow Progenitor Cells Functional Cells Healthy Cardiac Output Where Do Cardiac Progenitor Cells Come From?
  37. 37. Cardiac Progenitor Cell Restoration A progenitor cell differentiates into specific cell types and is more tissue-specific than a stem cell. Cardiac progenitor cells differentiate into functional cells in the heart. Progenitor cell restoration and renewal may reverse chronic heart failure.
  38. 38. Progenitor Cell Self-Renewal and Differentiation
  39. 39. How to Get More Healthy Progenitor Cells 1) Prompt old progenitor cells to self-renew 2) Restore production of new progenitor cells 1) Multiply patient’s progenitor cells in culture and administer back to patient.
  40. 40. Adult stem cells lose ability to repopulate tissues with functional cells Systemic deterioration occurs as functional cells degenerate/die Khorraminejad-Shirazi M et al., Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving higher efficacy in stem cell therapy. Hematol Oncol Stem Cell Ther (2017)  Boost cellular AMPK  Suppress excess mTORC1  Replenish NAD+ cell levels  Activate sirtuin proteins How your stem cells may be renewed:
  41. 41. “Aged‐senescent cells contribute to impaired heart regeneration.” Aging Cell; June 2019 Senescent Cells Thwart Heart Regeneration “The present findings provide new insights into therapies that target senescent cells to prevent an age- related loss of regenerative capacity.”
  42. 42. New Avenues for Improved Cardiac Regeneration Therapy Length‐independent telomere damage occurs in aging post‐mitotic cardiomyocytes. Mitochondrial dysfunction and reactive oxygen species drive telomere dysfunction in aged cardiomyocytes. Senescent cell clearance reduces hypertrophy and fibrosis in aged hearts. Findings on potential cardiac regeneration using senolytics: DOI 10.15252/embj.2018100492 Published online 08.02.2019 The EMBO Journal (2019)
  43. 43. Initial Data Reported Human Senolytic Study RAADFest-Sept 21, 2018 Two doses of dasatinib + quercetin in osteoarthritis patients:  82% of subjectssee relief of osteoarthritispain + improved jointfunction  Most subjects want to re-dose (after 6 months) to see better results  Waiting for follow-up results of MRI scans of joints & aging biomarkers (Most study subjects had severe bone-on-bone osteoarthritis)
  44. 44. Senolytic Dose Schedule Quercetin 25 mg per kilogram of body weight is approximately: 100 pounds = 1,125 mg 165 pounds = 1,875 mg 220 pounds = 2,500 mg 275 pounds = 3,000 mg 330 pounds = 3,750 mg Dasatinib 2.5 mg per kilogram of body weight is approximately: 100 pounds = 112 mg 165 pounds = 187 mg 220 pounds = 250 mg 275 pounds = 305 mg 330 pounds = 375 mg Take first dose of quercetin/dasatinib (preferably on empty stomach) then repeat same dose one week later. (May repeat this protocol in 6-12 months, or sooner as your doctor may direct.) Possible side effects include: Mild flu symptoms, diarrhea, headache, fatigue for 12-24 hours. One quercetin + dasatinib dose once a week for two weeks only (two total doses) doses) Caution: Take in presence of qualified medical doctor in case of severe allergic reaction. Do not engage in strenuous exercise during or for one week after the dosing schedule.
  45. 45. How to Obtain Dasatinib Provides two doses (160 mg each dose) to be taken one week apart for only two consecutive weeks. Lower Cost Alternative (Doctor’s prescription needed in either case) For physician listing and compounding pharmacy sources: age-reversal.net Four tablets cost $2,200 in United States Compounding pharmacy offers dasatinib for around $225
  46. 46. Dasatinib Potency Verified by Independent Assay HPLC (high-performance liquid chromatography) testing of a Lucius Lucidas (dasatinib) 50 mg tablet purchased from Bonhoa, and a Sprycel dasatinib (Bristol-Myers Squibb) 60 mg tablet purchased from the Indian pharmacy Vea Impex against a generic (known) quality of dasatinib acquired from Sigma (CAS: 302962-49-8), and Sprycel dasatinib (Bristol- Myers Squibb) 20 mg from a US pharmacy.
  47. 47. https://www.sciencedirect.com/science/article/pii/S2213231716303512
  48. 48. Too Wealthy to Die at Age 65 Paul Allen, Chairman of the Seattle Seahawks co-founded Microsoft in 1975. Diagnosed and treated for non-Hodgkin lymphoma in 2009. Cancer returned in 2018. He died from septic shock. Paul Allen was philanthropist and donated to medical research… but did NOT make it his priority! https://www.nytimes.com/2018/10/15/obituaries/paul-allen-dead.html Paul Allen (1953-2018) Net worth > $26.1 billion Expiration date: Oct. 15, 2018
  49. 49. https://jhoonline.biomedcentral.com/articles/10.1186/s13045-018-0608-2 • “Inhibitors of BCL-2…were shown to selectively induce apoptosis in malignant cells…” • “Extensively investigated…in several malignancies, including acute leukemia, lymphomas, and solid tumors.” • “…important role played by BCL-2 for cancer development…made it a relevant target for…solid tumors and hematological neoplasias”. May 11, 2018 “BCL-2 as therapeutic target for hematological malignancies” Journal of Hematology and Oncology Journal of Hematology & Oncology volume 11, Article number: 65 (2018)
  50. 50. BCL-2 as therapeutic target for hematological malignancies https://jhoonline.biomedcentral.com/articles/10.1186/s13045-018-0608-2 May 11, 2018 Case researchers discover gene that stops cancer cell proliferation Increased resistance to apoptosis is a key oncogenic mechanism in several hematological malignancies and, in many cases, especially in lymphoid neoplasias, has been attributed to the upregulation of BCL-2. Journal of Hematology and Oncology
  51. 51. Adapted from “Bcl-2 on the brink of breakthroughs in cancer treatment” by JC Reed, Cell Death and Differentiation, 2018; 25: 3-6. Based on data available at www.clinictrials.gov, the figure indicates molecules targeting Bcl-2 family of proteins that are currently in clinical development. The sponsors of the molecules are indicated by color, as shown at the bottom. Molecules in clinical development that target Bcl-2 family proteins Authors conclusion: “Bcl-2 family of proteins are now considered as promising drug targets with the potential to provide significant advances in the standard of care for patients suffering from oncological maladies and possibly for certain non-oncological diseases as well.” Take home message: Since natural polyphenols from black and green tea are demonstrated to be powerful suppressants of Bcl-2 family of proteins, their consumption for preventive reasons or for therapeutic management of cancer in addition to a conventional medicine standard of care is recommended.
  52. 52. Publication Summary of Results Take home message 1. Inhibition of spontaneous formation of lung tumors and rhabdomyosarcomas in A/J mice by black and green tea Carcinogenesis. 1998;19:501–507. Mice spontaneously developing rhabdomyosarcoma and lung cancer that were treated with black (2%) and green (1%) tea infusions for 52 weeks had 45% and 34% lower lung tumor incidence compared to the control group that was not treated with black and green tea. Furthermore, mice receiving black tea also had a profound 58% decrease in rhabdomyosarcoma incidence vs. the untreated group. Cancer develops in response to a variety of “stress-inducing” signals. Development and progression of various cancers are supported by different mechanisms. However, regardless of the type of cancer, the stress that triggers it and/or the mechanism that drives its progression, natural polyphenols from black and green tea were demonstrated to be a powerful suppressant of carcinogenesis in a variety of distinct animal models of cancer. 2. Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea Cancer Res. 2005;65:10623–10631. Administration of Epigallocatechin gallate (EGCG) at doses of 0.08% or 0.16% in drinking fluid decreased intestinal cancer formation in mice prone to developing this type of cancer by 37% or 47%, respectively. 3. Topical applications of caffeine or (-)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice Proc Natl Acad Sci U S A. 2002;99:12455–12460. Topical applications of EGCG (6.5 mM applied 5 days a week for 18 weeks) in a hairless mice highly prone to developing skin cancer after exposure to UVB decreased the number of nonmalignant and malignant tumors by 55% and 66%, respectively. EGCG increased apoptosis of the squamous cell carcinomas but had no effect on nontumor areas of the skin. 4. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate Cancer Lett. 1995;96:239–243. Administration of EGCG into nude mice developing prostate and breast cancers in response to inoculation with human prostate cancer and human breast cancer cells inhibited tumor growth. 5. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols Proc Natl Acad Sci U S A. 2001;98:10350–10355. A human achievable dose of green tea (equivalent to six cups of green tea/day) administered orally was demonstrated to delay the onset as well as reduce the tumor burden in mice that spontaneously develop prostate cancer. Natural polyphenols from black and green tea reduce incidence of several types of cancers in animal models
  53. 53. Natural polyphenols from black and green tea decrease cancer incidence and burden in humans Publication Summary of Results Take home message 6. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study Cancer Res. 2006;66(2):1234–1240. Daily consumption of 600 mg/day of green tea catechins for 12 months reduced prostate cancer incidence 10-fold in men initially diagnosed with high-grade prostate intraepithelial neoplasia that often progresses to prostate cancer. Initial human studies have provided unconvincing results for cancer preventive activities of green and black tea polyphenols. The activities of these natural polyphenols in the initial clinical trials were not as strong as polyphenol anti- cancer effects observed in animal models. Use of improved formulations that included higher polyphenol doses, increased purity and better bioavailability yielded encouraging results which suggest that green and black tea polyphenols are indeed cancer preventive in humans. 7. Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol Biomark Prev. 2008;17:3020–3025. Supplementation with 2.5 g of green tea extract daily for 12 months resulted in 50% reduction in the metachronous colorectal adenoma burden. 8. Phase 2 trial of daily, oral Polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Cancer. 2013;119(2):363–370. Polyphenon E with a standardized dose of EGCG (2000 mg per dose) was administered twice daily for 6 months to patients with early stage chronic lymphocytic leukemia (CLL). It was demonstrated that oral EGCG in the Polyphenon E preparation was well tolerated. Furthermore, CLL patients experienced a significant (up to 50%) reduction in palpable lymphadenopathy and approximately 20% decrease in the absolute lymphocyte count. 9. Green tea consumption and hematologic malignancies in Japan: the Ohsaki study Am J Epidemiol. 2009;170(6):730–738. A significant inverse association between green tea consumption and the risk of hematologic malignancies was found in a large population-based cohort of Japanese. Those who consumed >5 cups/day of green tea had a 42% lower risk of hematologic malignancies and a 48% lower risk of lymphoid neoplasms relative to study participants who consumed less than 1 cup/day of green tea.
  54. 54. Publication Summary of Results Take home message 10. Inhibition of carcinogenesis by tea Annu Rev Pharmacol Toxicol. 2002;42:25-54. Epigallocatechin gallate (EGCG), the main and most active polyphenolic compound from green tea, as well as other bioactive polyphenols found in black tea such as theaflavins are being evaluated in a context of their ability to prevent cancer cell survival in several cancer cell lines. Cancer cell survival can be inhibited by natural polyphenols present in green and black tea. 11. Inhibition of carcinogenesis by tea constituents Semin Cancer Biology. 2007; 17, 395-402 12. Molecular targets for the cancer preventive activity of tea polyphenols Mol Carcinog. 2006;45(6):431-435. 13. Tea polyphenols prevent lung from preneoplastic lesions and effect p53 and bcl-2 gene expression in rat lung tissues Int J Clin Exp Pathol. 2013;6(8):1523-1531. Consumption of 0.3% solution of green tea polyphenols profoundly decreased carcinogen-induced lung cancer development by reducing the precancerous lesions. The main mechanism reducing the burden of bronchial epithelial lesions was green tea-induced suppression in Bcl-2 expression. Natural polyphenols are anti-cancerogenic as they inhibit cancer cell survival supported by Bcl-2 family of proteins. Natural polyphenols either suppress activity or expression of Bcl-2 family of proteins, thereby triggering cell death in cancer cells. 14. Mechanisms of cancer prevention by green and black tea polyphenols Anticancer Agents Med Chem. 2006;6(5):389-406. ECGC and other green and black tea polyphenols induced cell cycle arrest, telomere fragmentation and apoptosis in human cancer cell lines. ECGC induced cancer cell apoptosis by inhibiting Bcl-2 activity. 15. Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells Oncogene. 2003;22(31):4851-4859. EGCG induced apoptosis in human prostate carcinoma LNCaP cell line by decreasing the expression of Bcl-2. 16. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins Cancer Res. 2003 Dec 1;63(23):8118-8121. Green tea catechins and black tea theaflavins are discussed as being very potent inhibitors of the antiapoptotic Bcl-2-family proteins, Bcl-xL and Bcl-2. Natural polyphenols from black and green tea induce cancer cell death via suppression of B-cell lymphoma-2 (Bcl-2) family of proteins
  55. 55. Costs about $72 a year
  56. 56. Dasatinib Potency Verified by Independent Assay HPLC (high-performance liquid chromatography) testing of a Lucius Lucidas (dasatinib) 50 mg tablet purchased from Bonhoa, and a Sprycel dasatinib (Bristol-Myers Squibb) 60 mg tablet purchased from the Indian pharmacy Vea Impex against a generic (known) quality of dasatinib acquired from Sigma (CAS: 302962-49-8), and Sprycel dasatinib (Bristol- Myers Squibb) 20 mg from a US pharmacy.
  57. 57. Dasatinib C Potency Verified by Independent Assay Can cost under $150 a year
  58. 58. Senolytic Dose Schedule Quercetin 25 mg per kilogram of body weight is approximately: 100 pounds = 1,125 mg 165 pounds = 1,875 mg 220 pounds = 2,500 mg 275 pounds = 3,000 mg 330 pounds = 3,750 mg Dasatinib 2.5 mg per kilogram of body weight is approximately: 100 pounds = 112 mg 165 pounds = 187 mg 220 pounds = 250 mg 275 pounds = 305 mg 330 pounds = 375 mg Take first dose of quercetin/dasatinib (preferably on empty stomach) then repeat same dose one week later. (May repeat this protocol in 6-12 months, or sooner as your doctor may direct.) Possible side effects include: Mild flu symptoms, diarrhea, headache, fatigue for 12-24 hours. One quercetin + dasatinib dose once a week for two weeks only (two total doses) doses) Caution: Take in presence of qualified medical doctor in case of severe allergic reaction. Do not engage in strenuous exercise during or for one week after the dosing schedule.
  59. 59. Senolytic Update October 3rd 2019

×