Unified Theory of Stem Cell Rejuvenation

1. Unified Theory of Stem Cell Rejuvenation William Faloon American Academy of Stem Cell Physicians Zoom Conference July 21, 2021

2. age-reversal.net This entire presentation and info about our research available at:

3. Life Extension® was born in: January 1977  Life Extension® incorporated in 1977 in Florida.  First published in 1980. (Anti-Aging News)  World’s largest anti-aging organization…over 400,000 supporters. (2021) Life Extension Center-Pompano Beach, Florida (1977)

4. Reduce Bone Facture Risks

8. 1980-1986-Anti-Aging News 1986-1994-Life Extension Report 1994-2021-Life Extension Magazine 41 Consecutive Years of Monthly Publication (400,000 copies mailed each month)

9. Our Controversial Contention It may be possible… To Reverse Aging in Humans Today www.age-reversal.net

10. Adult stem cells lose ability to repopulate tissues with functional cells. Systemic deterioration occurs as functional cells degenerate. 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+  Activate sirtuin proteins  Remove senescent cells How your stem cells may be renewed:

11. “A triple drug combination has been used to extend the lifespan of fruit flies by 48% in a new study.” https://www.nextbigfuture.com/2019/10/rapamycin-and-two-other-drugs-extends-lifespan-twice-as-much-as-any-other-drug-combo.html Rapamycin and Two Other Drugs Extends Lifespan Twice As Much As Any Other Drug Combo

12. “Previousstudiesinfruitflieshave achievedlifespan extensions ofabout 5-20% …sowefounditwasquiteremarkable thatthisdrugcombinationenabled themtolive Castillo-Quan, Jorge Iván, Luke S. Tain, Kerri J. Kinghorn, Li Li, Sebastian Grönke, Yvonne Hinze, T. Keith Blackwell, Ivana Bjedov, and Linda Partridge. "A triple drug combination targeting components of the nutrient-sensing network maximizes longevity." Proceedings of the National Academy of Sciences 116, no. 42 (2019): 20817-20819. September 30, 2019 Combined Interventions More Effective than SingleAgent Therapy

13. Rapamycin Lithium Senolytic + + Fruit Fly Lifespan Extension by 48%3 = This study supports a scientific approach to enable longer lifespans. October 15, 2019 1) Rapamcyin benefits can partially occur when AMPK is activated. 2) Health-conscious people today are utilizing senolytics. 3) Multi-model therapies needed to achieve lifespan extension “A triple drug combination targeting components of the nutrient-sensing network maximizes longevity” PNAS October 15, 2019 116 (42) 20817-20819 https://doi.org/10.1073/pnas.1913212116

14.  Each compound individually extended lifespan by 11%  Pairing two extended lifespan roughly 30%  Three combined extended lifespan by 48% Castillo-Quan, Jorge Iván, Luke S. Tain, Kerri J. Kinghorn, Li Li, Sebastian Grönke, Yvonne Hinze, T. Keith Blackwell, Ivana Bjedov, and Linda Partridge. "A triple drug combination targeting components of the nutrient-sensing network maximizes longevity." Proceedings of the National Academy of Sciences 116, no. 42 (2019): 20817-20819. Combination Treatments are Essential When fruit flies receive lithium, rapamycin, senolytic separately and/or in combination:

15. Stem Cells Bone Marrow Progenitor Cells Functional Cells Healthy Organ Function Where Do Progenitor Cells Come From?

16. “Aged‐senescent cells contribute to impaired heart regeneration.” Aging Cell; June 2019 Senescent Cells Preclude Regeneration “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…” Se Heart Failure Epidemic Senescent cells secrete protein-degrading enzymes and inflammatory factors that destroy healthy cells and preclude stem cell regeneration.

17. Senolytics Restore Heart Regenerative Capacity Jan. 31, 2019 “The present findings provide new insights into therapies that target senescent cells to prevent an age- related loss of regenerative capacity.” Reference: “Aged‐senescent cells contribute to impaired heart regeneration.” Aging Cell;

18. O R I GI N A L PAPER Aged‐senescent cells contribute to impaired heart regeneration Fiona C. Lewis‐McDougall1 | Prashant J. Ruchaya1 | Eva Domenjo‐Vila1 | Tze Shin Teoh1 | Larissa Prata2 | Beverley J. Cottle1 | James E. Clark3 | Prakash P. Punjabi4 | Wael Awad5 | Daniele Torella6 | Tamara Tchkonia2 | James L. Kirkland2 | Georgina M. Ellison‐Hughes1 Reference: “Aged‐senescent cells contribute to impaired heart regeneration.” Aging Cell; Jan 31 2019 “Therapeutic approaches that eliminate senescent cells…may restore the regenerative capacity of the heart.” January 31 2019

19. 2021 2030

20. AMPK Activation (metformin) Step 1:

21. “Reversal of epigenetic aging and immunosenescent trends in humans.” Aging Cell; Sept 2019 Human Age Reversal Demonstrated in 2019 1) Human growth hormone 2) DHEA 3) Metformin Study conducted by Dr. Greg Fahy in collaboration with researchers from Stanford University and UCLA consisted of individualized doses of: Study subjects also provided with daily vitamin D3 and zinc.

22. https:// www.dailymail.co.uk/health/article-7435427/ Oct.22,2019 Turning Back Time! “Aging is REVERSED in men using a cocktail of growth hormones and diabetes drugs in study that saw test group shed 2.5 biological years.”

23. Nov 29, 2015

24. April 24, 2016

25. https://www.webmd.com/healthy-aging/story/is-there-a-cure-for-aging February 20, 2021 “If the results are what they think they will be, the whole world could go on metformin and extend life for everybody.” - Nir Barzilai, lead researcher on “Targeting Aging with Metformin” Clinical Trial

26. Type II diabetics taking metformin: United Kingdom Diabetes Study ►32% reduced risk of diabetic complications ►42% reduced risk for diabetes-related death ►36% reduced all-cause mortality risk Study results published January 1995 British Medical Journal; Jan 14, 1995;” United Kingdom Prospective Diabetes Study (UKPDS)

27. Life Extension Magazine recommended metformin 26 years ago…the FDA went berserk! March 1995

30. Diabetics taking metformin have lower cancer rates Metformin Prevents Cancer MD Anderson Cancer Center found risk of pancreatic cancer was 62% lower in diabetics using metformin. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009 Aug;137(2):482-8.

31. Decades of research reveals disease-fighting impact of metformin. November 2010

32. Study Results Found on March 21st 2017 Journal of the American Medical Association JAMA. Published online March 21, 2017. doi:10.1001/jama.2016.17844 Metformin studied in prediabetic patients. Compared to placebo 850 mg of metformin two times a day: Reduced type II diabetes risk 31% In patients under age 60: metformin reduced diabetic risk by 58%. “Metformin can cause weight loss…” Quote:

33. Sept. 2017 Metformin Demonstrates Therapeutic Effects Against Colon Cancer Am J Med Sci. 2017 Sep;354(3):246-251. doi: 10.1016/j.amjms.2017.05.006. Epub 2017 May 19. Metformin Has Positive Therapeutic Effects in Colon Cancer and Lung Cancer. Colon Cancer Metformin Patients Non-Metformin Patients Recurrences 4% 19% Metastases 23% 46% 5-Year Survival 57% 37% Deaths 48% 76% (Metformin boosts AMPK activity and indirectly inhibits mTOR) “Metformin therapy is associated with significantly better prognosis in patients with colon cancer” Caveat: Some diabetics in control group treated with insulin or sulfonylurea drugs that promote tumor cell propagation. Diabetics on metformin showed these benefits compared to diabetics not prescribed metformin:

34. Example of Lethal Delay https://www.longevity.technology/worlds-first-anti-aging-trial-gets-green-light/ Sept 4, 2019 1958 - Metformin approved as anti-diabetic drug in England 1995 - Life Extension® lists metformin as anti-aging drug 2015 - FDA approves first anti-aging study of a drug (metformin) 2019 - Metformin study receives $75 million funding ($40 million from anonymous donor)

35. Catastrophic Loss of Life A 2019 study tabulated reductions in cardiovascular mortality in type II diabetics using metformin.1 Life Extension® calculated how many cardiovascular deaths may have occurred in response to metformin’s 37-year delay. This exceeds the death toll of all wars America has ever fought. 1. Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function. JAMA. 2019 September 19:1-11. Almost 4 million American diabetics may have died because of the delay in this one drug (metformin) becoming available.

36. The subcutaneous administering of 9 million international units a day of the drug interleukin-2 to pancreatic cancer patients three days before surgery: Interleukin-2 versus Placebo In Pancreatic CancerTreatment Two-Year Survival Three-Year Survival Postoperative Complications Interleukin-2 Group Control (Saline) Group 33% 1o% 22% O% 33% 8O%

37. Complete response of stage IV pancreatic cancer combining checkpoint inhibitors + interleukin-2 + hyperthermia March 2019 Results: First restaging 11/2017 three month following initiation of therapy with CT of abdomen and pelvis demonstrated major partial remission with decrease of the size of disseminated liver metastasis and no measurable primary pancreatic tumor, vanishing of the previously described lymphadenopathy. At that time the patient had started gaining weight again and was free of any cancer-related symptoms. Second restaging 05/2018 nine months following initiation of therapy with CT of the abdomen and indicated complete remission. Follow-up time now is 1½ years. Patient is healthy and free of any symptoms. Conclusion: This is one of several cases of advanced stage cancer patients having a complete response to primary immunotherapy treatment. Clearly, this combination immune therapy warrants further clinical studies. https://www.alliedacademies.org/proceedings/complete-response-of-stage-iv-pancreatic-cancer-combining-lowdose-checkpoint-inhibitors-with-interleukin2-il2-and-fever--4289.html

38. Not Supplemented with melatonin: 5.34 Years Supplemented with 3 mg of melatonin: 12.8 Years Seven-year increased survival in melatonin-treated patients after conventional treatment failure. Survival of Prostate Cancer Patients with Poor Prognosis: Melatonin Doubles Human Survival https://www.oncotarget.com/article/27757/text/

39. November 29 ,2020 https://pubmed.ncbi.nlm.nih.gov/33251599/#:~:text=Abstract,anticancer%20activity%20in%20experimental%20investigations “Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower levels of melatonin.”

40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370547/ Soaring Numbers of Published Studies on “Melatonin and Cancer”: 1981-2019

41.  20 mg melatonin as an adjunctive to standard chemo treatment.  Reduced risk of death by 39%.  Individuals with normal baseline sleep median survival 17.6 months with evening melatonin compared to 10.4 months in placebo group. Daily evening melatonin prolongs survival among patients with advanced non-small-cell lung cancer March 12, 2021 https://www.tandfonline.com/doi/full/10.1080/09291016.2021.1899485?scroll=top&needAccess=true& Acknowledgments We would like to thank William Faloon of Life Extension Foundation for providing melatonin and placebo.

42. National Library of Medicine Titles and Descriptions of Published Studies About Melatonin and Cancer Melatonin and Cancer Hallmarks. Talib WH.Molecules. 2018 Feb 26;23(3):518. doi: 10.3390/molecules23030518.PMID: 29495398 Free PMC article. Review. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, metastasis, replicative immortality, angiogenesis, resisting cell death, altered cell … Melatonin for the prevention and treatment of cancer. Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB. Oncotarget. 2017 Jun 13;8(24):39896-39921. doi: 10.18632/oncotarget.16379.PMID: 28415828 Free PMC article. Review. Melatonin could also be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. Melatonin could be an excellent candidate for the prevention and treatment of several … Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K.Int J Mol Sci. 2017 Apr 17;18(4):843. doi: 10.3390/ijms18040843.PMID: 28420185 Free PMC article. Review. Many studies have shown that melatonin's co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sen …

43. Melatonin and breast cancer: Evidences from preclinical and human studies. Kubatka P, Zubor P, Busselberg D, Kwon TK, Adamek M, Petrovic D, Opatrilova R, Gazdikova K, Caprnda M, Rodrigo L, Danko J, Kruzliak P.Crit Rev Oncol Hematol. 2018 Feb;122:133-143. doi: 10.1016/j.critrevonc.2017.12.018. Epub 2017 Dec 29.PMID: 29458781 Review. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. ...This correlation was confirmed by ob … Melatonin and (-)-Epigallocatechin-3-Gallate: Partners in Fighting Cancer. Zhang L, He Y, Wu X, Zhao G, Zhang K, Yang CS, Reiter RJ, Zhang J.Cells. 2019 Jul 19;8(7):745. doi: 10.3390/cells8070745.PMID: 31331008 Free PMC article. The current work investigated the influence of melatonin on the oncostatic activity of EGCG in two cancer cell lines, wherein melatonin induced an opposite response of p21. In human tongue cancer TCA8113 cells, melatonin-induced p21 and EGCG-med … Melatonin and pancreatic cancer: Current knowledge and future perspectives. Tamtaji OR, Mirhosseini N, Reiter RJ, Behnamfar M, Asemi Z.J Cell Physiol. 2019 May;234(5):5372-5378. doi: 10.1002/jcp.27372. Epub 2018 Sep 19.PMID: 30229898 Review. Melatonin is a potent antioxidant and tissue protector against inflammation and oxidative stress. In vivo and in vitro studies have shown that melatonin supplementation is an appropriate therapeutic approach for pancreatic cancer. ...Limited clinical studies, … Melatonin Differentially Modulates NF-кB Expression in Breast and Liver Cancer Cells. Colombo J, Jardim-Perassi BV, Ferreira JPS, Braga CZ, Sonehara NM, Júnior RP, Moschetta MG, Girol AP, Zuccari DAPC.Anticancer Agents Med Chem. 2018;18(12):1688-1694. doi: 10.2174/1871520618666180131112304.PMID: 29384062 Melatonin has oncostatic, antiangiogenic and antimetastatic properties, and some recent studies have indicated an inhibitory effect of melatonin on NF-kB in some types of cancer. This work aims to investigate the effects of melatonin treatment on the e …

44. Melatonin and Respiratory Diseases: A Review. Habtemariam S, Daglia M, Sureda A, Selamoglu Z, Gulhan MF, Nabavi SM.Curr Top Med Chem. 2017;17(4):467-488. doi: 10.2174/1568026616666160824120338.PMID: 27558675 Review. There are numerous scientific reports on the therapeutic potential of melatonin in treatment of asthma, respiratory diseases for infections, chronic obstructive pulmonary disease, lung cancer, pleural cavity diseases, as well as vascular pulmonary disease. In the pr … Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment. Farhood B, Goradel NH, Mortezaee K, Khanlarkhani N, Najafi M, Sahebkar A.J Cell Physiol. 2019 May;234(5):5613-5627. doi: 10.1002/jcp.27391. Epub 2018 Sep 21.PMID: 30238978 Review. Evidence suggests that genomic instability is responsible for cancer incidence after exposure to carcinogenic agents, and increases the risk of secondary cancers following treatment with radiotherapy or chemotherapy. Melatonin as the main product of the pinea … Melatonin Inhibits Reactive Oxygen Species-Driven Proliferation, Epithelial-Mesenchymal Transition, and Vasculogenic Mimicry in Oral Cancer. Liu R, Wang HL, Deng MJ, Wen XJ, Mo YY, Chen FM, Zou CL, Duan WF, Li L, Nie X.Oxid Med Cell Longev. 2018 Mar 21;2018:3510970. doi: 10.1155/2018/3510970. eCollection 2018.PMID: 29725496 Free PMC article. Globally, oral cancer is the most common type of head and neck cancers. Melatonin elicits inhibitory effects on oral cancer; however, the biological function of melatonin and underlying mechanisms remain largely unknown. ...Mela … Melatonin and its ubiquitous anticancer effects. Bhattacharya S, Patel KK, Dehari D, Agrawal AK, Singh S.Mol Cell Biochem. 2019 Dec;462(1-2):133-155. doi: 10.1007/s11010-019-03617-5. Epub 2019 Aug 26.PMID: 31451998 Review. In this review, the underlying anticancer mechanisms of Melatonin such as stimulation of apoptosis, Melatonin receptors (MT1 and MT2) stimulation, paro-survival signal regulation, the hindering of angiogenesis, epigenetic alteration and metastasis have …

45. Cancer metastasis: Mechanisms of inhibition by melatonin. Su SC, Hsieh MJ, Yang WE, Chung WH, Reiter RJ, Yang SF.J Pineal Res. 2017 Jan;62(1). doi: 10.1111/jpi.12370. Epub 2016 Nov 25.PMID: 27706852 Review. Recently, however, interest has shifted toward the role of melatonin on tumor metastases. In this review, we highlight current advances in understanding the molecular mechanisms by which melatonin counteracts tumor metastases, including experimental and clini … The effect of melatonin on sleep and quality of life in patients with advanced breast cancer. Innominato PF, Lim AS, Palesh O, Clemons M, Trudeau M, Eisen A, Wang C, Kiss A, Pritchard KI, Bjarnason GA.Support Care Cancer. 2016 Mar;24(3):1097-105. doi: 10.1007/s00520-015-2883-6. Epub 2015 Aug 11.PMID: 26260726 Clinical Trial. In this prospective phase II trial, we sought to assess the effect of melatonin on circadian biomarkers, sleep, and quality of life in breast cancer patients. ...CONCLUSION: These results invite further investigation of melatonin as a potentially usefu … Melatonin, an inhibitory agent in breast cancer. Nooshinfar E, Safaroghli-Azar A, Bashash D, Akbari ME.Breast Cancer. 2017 Jan;24(1):42-51. doi: 10.1007/s12282-016-0690-7. Epub 2016 Mar 26.PMID: 27017208 Review. BACKGROUND: The heterogeneous nature of breast cancer makes it one of the most challenging cancers to treat. Due to the stimulatory effect of estrogen in mammary cancer progression, anti-estrogenic agents like melatonin have found their way into breast … Melatonin: A Molecule for Reducing Breast Cancer Risk. González-González A, Mediavilla MD, Sánchez-Barceló EJ.Molecules. 2018 Feb 6;23(2):336. doi: 10.3390/molecules23020336.PMID: 29415446 Free PMC article. Review. The objective of this article is to review the basis supporting the usefulness of melatonin as an adjuvant therapy for breast cancer (BC) prevention in several groups of individuals at high risk for this disease. Melatonin, as a result of its antiestrogenic … Molecular and Cellular Mechanisms of Melatonin in Osteosarcoma. Lu KH, Lin RC, Yang JS, Yang WE, Reiter RJ, Yang SF.Cells. 2019 Dec 12;8(12):1618. doi: 10.3390/cells8121618.PMID: 31842295 Free PMC article. Review.

46. The potential therapeutic actions of melatonin in colorectal cancer. Chok KC, Ng CH, Koh RY, Ng KY, Chye SM.Horm Mol Biol Clin Investig. 2019 May 29;39(1):/j/hmbci.2019.39.issue-1/hmbci-2019-0001/hmbci- 2019-0001.xml. doi: 10.1515/hmbci-2019-0001.PMID: 31141480 Review. Colorectal cancer (CRC) is the third most common cancer and lethal disease worldwide. Melatonin, an indoleamine produced in pineal gland, shows anticancer effects on a variety of cancers, especially CRC. ...Next, we review the role of melaton … Modulation of apoptosis by melatonin for improving cancer treatment efficiency: An updated review. Mortezaee K, Najafi M, Farhood B, Ahmadi A, Potes Y, Shabeeb D, Musa AE.Life Sci. 2019 Jul 1;228:228-241. doi: 10.1016/j.lfs.2019.05.009. Epub 2019 May 8.PMID: 31077716 Review. Melatonin is a potent natural antioxidant and anti-inflammatory agent that protects against toxic side effects of radiation and chemotherapy. Furthermore, in some cancer cells, melatonin aids sensitizing cancer cells to therapy. Apoptosis … Therapeutic Opportunities in Colorectal Cancer: Focus on Melatonin Antioncogenic Action. Wu H, Liu J, Yin Y, Zhang D, Xia P, Zhu G.Biomed Res Int. 2019 Sep 17;2019:9740568. doi: 10.1155/2019/9740568. eCollection 2019.PMID: 31637261 Free PMC article. Review. Colorectal cancer (CRC) influences individual health worldwide with high morbidity and mortality. Melatonin, which shows multiple physiological functions (e.g., circadian rhythm, immune modulation, and antioncogenic action), can be present in almost al … [The influence of melatonin on the immune system and cancer]. Vinther AG, Claësson MH.Ugeskr Laeger. 2015 May 18;177(21):V10140568.PMID: 26027592 Review. Danish. Melatonin has been shown to play a fundamental part in neuroimmunomodulation. Besides regulating the circadian rhythm it works as a natural antioxidant with immune stimulatory and anti-cancer properties. Melatonin is a regulator of haemopoiesis and …

49. Melatonin: A new inhibitor agent for cervical cancer treatment. Shafabakhsh R, Reiter RJ, Mirzaei H, Teymoordash SN, Asemi Z.J Cell Physiol. 2019 Dec;234(12):21670-21682. doi: 10.1002/jcp.28865. Epub 2019 May 27.PMID: 31131897 Review. Cervical cancer is one of the most common cancers between women and is known as the third leading cause of female cancer related deaths annually. ...Herein, for first time, we summarized anticervical cancer effects of melatonin and … Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer. Wojcik M, Krawczyk M, Wojcik P, Cypryk K, Wozniak LA.Curr Med Chem. 2017 Nov 20;24(35):3829-3850. doi: 10.2174/0929867324666170718110606.PMID: 28721827 Review. As increasing evidence shows beneficial effects of melatonin (MLT) on typical pathological changes occurring during the development of T2DM and cancer, the present review focuses on molecular aspects of antidiabetic and anticancer activities of MLT … Melatonin: an inhibitor of breast cancer. Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, Frasch T, Blask DE.Endocr Relat Cancer. 2015 Jun;22(3):R183-204. doi: 10.1530/ERC-15-0030. Epub 2015 Apr 15.PMID: 25876649 Free PMC article. Review. The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppress … Melatonin is a potential inhibitor of ovarian cancer: molecular aspects. Zare H, Shafabakhsh R, Reiter RJ, Asemi Z.J Ovarian Res. 2019 Mar 26;12(1):26. doi: 10.1186/s13048-019-0502-8.PMID: 30914056 Free PMC article. Revie Multiple studies have shown the significant beneficial roles of melatonin in various types of cancers including ovarian cancer. This paper aims to shed light on the roles of melatonin in ovarian cancer treatment from the standpoint of the molecu …

50. Melatonin: A new inhibitor agent for cervical cancer treatment. Shafabakhsh R, Reiter RJ, Mirzaei H, Teymoordash SN, Asemi Z.J Cell Physiol. 2019 Dec;234(12):21670-21682. doi: 10.1002/jcp.28865. Epub 2019 May 27.PMID: 31131897 Review. Cervical cancer is one of the most common cancers between women and is known as the third leading cause of female cancer related deaths annually. ...Herein, for first time, we summarized anticervical cancer effects of melatonin and … Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer. Wojcik M, Krawczyk M, Wojcik P, Cypryk K, Wozniak LA.Curr Med Chem. 2017 Nov 20;24(35):3829-3850. doi: 10.2174/0929867324666170718110606.PMID: 28721827 Review. As increasing evidence shows beneficial effects of melatonin (MLT) on typical pathological changes occurring during the development of T2DM and cancer, the present review focuses on molecular aspects of antidiabetic and anticancer activities of MLT … Melatonin: an inhibitor of breast cancer. Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, Frasch T, Blask DE.Endocr Relat Cancer. 2015 Jun;22(3):R183-204. doi: 10.1530/ERC-15-0030. Epub 2015 Apr 15.PMID: 25876649 Free PMC article. Review. The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor- mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppress … Melatonin is a potential inhibitor of ovarian cancer: molecular aspects. Zare H, Shafabakhsh R, Reiter RJ, Asemi Z.J Ovarian Res. 2019 Mar 26;12(1):26. doi: 10.1186/s13048-019-0502-8.PMID: 30914056 Free PMC article. Review. Multiple studies have shown the significant beneficial roles of melatonin in various types of cancers including ovarian cancer. This paper aims to shed light on the roles of melatonin in ovarian cancer treatment from the standpoint of the molecu …

51. Melatonin: A new inhibitor agent for cervical cancer treatment. Shafabakhsh R, Reiter RJ, Mirzaei H, Teymoordash SN, Asemi Z.J Cell Physiol. 2019 Dec;234(12):21670-21682. doi: 10.1002/jcp.28865. Epub 2019 May 27.PMID: 31131897 Review. Cervical cancer is one of the most common cancers between women and is known as the third leading cause of female cancer related deaths annually. ...Herein, for first time, we summarized anticervical cancer effects of melatonin and … Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer. Wojcik M, Krawczyk M, Wojcik P, Cypryk K, Wozniak LA.Curr Med Chem. 2017 Nov 20;24(35):3829-3850. doi: 10.2174/0929867324666170718110606.PMID: 28721827 Review. As increasing evidence shows beneficial effects of melatonin (MLT) on typical pathological changes occurring during the development of T2DM and cancer, the present review focuses on molecular aspects of antidiabetic and anticancer activities of MLT … Melatonin: an inhibitor of breast cancer. Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, Frasch T, Blask DE.Endocr Relat Cancer. 2015 Jun;22(3):R183-204. doi: 10.1530/ERC-15-0030. Epub 2015 Apr 15.PMID: 25876649 Free PMC article. Review. The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor- mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppress … Melatonin is a potential inhibitor of ovarian cancer: molecular aspects. Zare H, Shafabakhsh R, Reiter RJ, Asemi Z.J Ovarian Res. 2019 Mar 26;12(1):26. doi: 10.1186/s13048-019-0502-8.PMID: 30914056 Free PMC article. Review. Multiple studies have shown the significant beneficial roles of melatonin in various types of cancers including ovarian cancer. This paper aims to shed light on the roles of melatonin in ovarian cancer treatment from the standpoint of the molecu …

52. Melatonin and its anti-glioma functions: a comprehensive review. Maitra S, Bhattacharya D, Das S, Bhattacharya S.Rev Neurosci. 2019 Jul 26;30(5):527-541. doi: 10.1515/revneuro-2018-0041.PMID: 30645197 Review. Melatonin acts on specific receptors and has an important role in overall energy metabolism. This review encompasses several aspects of melatonin Melatonin as a potential anticarcinogen for non-small-cell lung cancer. Ma Z, Yang Y, Fan C, Han J, Wang D, Di S, Hu W, Liu D, Li X, Reiter RJ, Yan X.Oncotarget. 2016 Jul 19;7(29):46768-46784. doi: 10.18632/oncotarget.8776.P Non-small-cell lung cancer (NSCLC) is a leading cause of death from cancer worldwide. Melatonin, an indoleamine discovered in the pineal gland, ex Mitochondrial functions and melatonin: a tour of the reproductive cancers. de Almeida Chuffa LG, Seiva FRF, Cucielo MS, Silveira HS, Reiter RJ, Lupi LA.Cell Mol Life Sci. 2019 Mar;76(5):837-863. doi: 10.1007/s00018-018-2963-0. Moreover, melatonin promotes mitochondrial homeostasis by regulating nuclear DNA and mtDNA transcriptional activities. This review focuses on th

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54. Reducesenescentcells(senolytics) Step 2:

55. Senolytics are compounds that selectively destroy senescent cells.

56. Senescent cells accumulate with normal aging and: Removing Senescent Cells Confers Healthy Longevity

57. 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.

58. 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:

59. 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.

60. 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 younger Hair loss https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101/ Untreated Senolytic Treated Starting at Mid-Age

61. 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 younger Hair 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.

62. 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 younger Hair 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

63. Anti-Cancer Properties of Senolytics May. 17, 2019 https://science.sciencemag.org/content/364/6441/636.full “…elimination of senescent cells with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.”

64. 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.”

65. “Moreover, tremendous advances are being made in our understanding of the science of aging, yielding exciting potential treatments that may alter the course of this inevitable process.5 One aspect of this work relates to “senolytics,” the study of ways to either eliminate senescent cells that may have deleterious effects or slow or reverse the aging process by restoring cells’ lost function. “Enabling Healthful Aging for All — The National Academy of Medicine Grand Challenge in Healthy Longevity” https://www.nejm.org/doi/full/10.1056/NEJMp1912298?query=TOC October 31, 2019 “Enabling Healthful Aging for All…”

66. 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/

67. Deadly Impact of Senescent Cells July 9, 2018 “Senolytics improve physical function and increase lifespan in old age.” Nature Medicine, July 9th, 2018 Transplanting small numbers of senescent cells into young mice causes: 1) Persistent physical dysfunction. 2) Spread of cell senescence to host tissues.

68. Deadly Impact of Senescent Cells July 9, 2018 “This indicates potency of senescent cells in shortening healthspan/lifespan.” “Senolytics improve physical function and increase lifespan in old age.” Nature Medicine, July 9th, 2018 Transplanting senescent cells into older mice causes: 1) Degenerative pathologies 2) Reduced survival

69. 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

70. Senolytics Increase Lifespan in Old Age July 9, 2018 “Senolytics improve physical function and increase lifespan in old age.” Nature Medicine, July 9th, 2018 Dasatinib + quercetin selectively eliminated senescent cells and decrease secretion of frailty-related pro-inflammatory cytokines in human adipose explants. “Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health and lifespan in old mice.”

71. 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

72. 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

73. First Published Human Senolytic Clinical Trial Jan 7, 2019 THE LANCET

74. 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.”

75. 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.”

76. 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/

77.  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

78. “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

79. “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.”

80. Apr. 15, 2019 Senolytics 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

81. 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

82. 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.

83. 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.

84. “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.8,2019 British 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

85. “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."

86. 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)

87. https://www.sciencedirect.com/science/article/pii/S2213231716303512 Systemic Destructive Impact of the Senescent Cell Burden

88. 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 interpretation of MRI scans of joints (Most study subjects had severe bone-on-bone osteoarthritis)

89. 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.

90. 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.

91. Dasatinib C Potency Verified by Independent Assay Can cost under $150 a year

92. 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 $144 Provides two doses (200 mg each dose) to be taken o one week apart for only two consecutive weeks Tailor Made Compounding 200 Moore Drive Nicholasville, KY 40356 P : 1 (859) 887 0013 F : 1 (859) 406 1242 https://tailormadecompounding.com/contact-us/

93. Senolytic Activator with Bio-Fisetin

94. Once-A-Week Dosing Costs about $80 a year  Theaflavins (BCL2 inhibitor)  Bio-Fisetin (greater bioavailability)  Bio-Quercetin (greater bioavailability)  Apigenin (reduce SASPs) Senolytic Activator® nutrients:

95. Dr. Alan Green at his practice in Little Neck, NY now has 500+ patients using rapamycin with 100+ patient adding dasatinib, fisetin and quercetin . Dr. Green’s Anti-Aging Cocktail 1) Rapamycin 2) Dasatinib 3) Fisetin 4) Quercetin Now in Clinical Use: https://senolyticstreatment.com/

96. Dr. Alan Green’s Senolytic Protocol  Dasatinib: 100 mg a day for 3 days  Quercetin: 1000 mg a day for 3 days  Fisetin 1500 mg day for 3 days https://senolyticstreatment.com/ These are maximum doses. Patients determine sensitivity with smaller doses. For diseases like Alzheimer's, cardiomyopathy, pulmonary fibrosis, emphysema, fatty liver, chronic kidney disease, metabolic syndrome, obesity, frailty: 1-2 of these senolytic treatments a month For lifespan and healthspan: 4 treatments a year (3-month) interval

97. https://en.wikipedia.org/wiki/Sumner_Redstone Redstone built multi-billion-dollar empire. Donated >$216 million to charities. Boasted he would live forever. Dead at age 97 from dementia complications. Sumner Redstone 1923-2020 Expiration date: Aug. 11, 2020 Net worth > $3-4 billion

98. Multi-billionaire real estate developer dies of Covid-19 complications at age 78. Who missed the longevity boat? Stanley Chera (1942-2020) Expiration date: Apr. 10, 2020 Net worth > $4.3 billion https://nypost.com/2020/04/13/real-estate-mogul-stanley-chera-dead-at-78-from-coronavirus/ Net worth > $4.3 billion

99. David Koch, a billionaire industrialist, philanthropist died at 79 with assets worth nearly $50 billion. He was diagnosed with prostate cancer and in declining health. Who missed the longevity boat? David Koch (1940 - 2019) Expiration date: Aug. 23, 2019 Net worth > $50 billion https://www.cnn.com/2019/08/23/politics/david-koch-dead/

100. NAD+ restoration Step 3:

101. Australasian Research Institute What is NAD+ used for? NAD+ Energy production (ATP) DNA repair (PARP1 gene) Gene expression (Sirtuin 1-7) Immune Cell signalling Neurotransmitter (Brain health) Energy Enzyme activity (Longer telomeres?)

102. Sharp Drop in NAD+ Tissue Levels with Age

103. We Must Repair Our DNA  Each cell suffers 10 DNA breaks every day.1  Unrepaired DNA damage major factor in degenerative aging.  No one would voluntarily allow DNA repair to be “turned off”.  NAD+ depletion with aging “turns off” DNA repair enzymes 1.Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010;79:181-211. NAD+ restores cellular DNA repair

104. March 22, 2018 “We’ve discovered a way to reverse vascular aging by boosting the presence of naturally occurring molecules in the body that augment the physiological response to exercise.” The active molecules: SIRT1 and NAD+ David Sinclair, Ph.D. professor in the Department of Genetics at Harvard Medical School Impairment of an Endothelial NAD -H 2 S Signaling Network Is a Reversible Cause of Vascular Aging. Cell, 2018; 173 (1): 74 DOI: 10.1016/j.cell.2018.02.008

105. Anti-Aging Supplement That Experts Take “…researchers have found that re- upping NAD+ in older mice causes them to look and act younger, as well as live longer than expected.” Time Magazine-February 26 2018

106. Is an Anti-Aging Pill on the Horizon? “NAD+ is the closest we’ve gotten to a fountain of youth,” says David Sinclair (Harvard Medical School). “It’s one of the most important molecules for life to exist, and without it, you’re dead in 30 seconds.” http://amp.timeinc.net/time/5159879/is-an-anti-aging-pill-on-the-horizon?__twitter_impression=true February 26, 2018

107. May 21, 2018 NAD+ May Improve Heart Function ”Stabilizing the intracellular NAD+ level represents a promising therapeutic strategy to improve myocardial bioenergetics and cardiac function.“ “In this issue of Circulation, Diguet et al5 report exciting data suggesting that supplementation with a NAD+ precursor, nicotinamide riboside, reduces cardiac dysfunction in preclinical models of heart failure.” http://circ.ahajournals.org/content/137/21/2274 (NAD+ patches or infusions needed for humans to obtain equivalent dose.)

108. Improvements in glaucoma/eyesight observed in a number of elderly humans given NAD+ infusions in recent clinical trial. . NAD+ May Protect and Restore Eyesight Published studies suggest NAD+ or sirtuin enhancers may*: *“NAD+ and sirtuins in retinal degenerative diseases: A look at future therapies.” Progress in Retinal and Eye Support; June 12, 2018

109.  Enhanced muscle function;  Protection of muscle, neural, and melanocyte stem cells;  Extended lifespan. NAD+ Protects Stem Cells in Aging Mice NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 17 Jun 2016: Vol. 352, Issue 6292, pp. 1436-1443 DOI: 10.1126/science.aaf2693

110. NAD+ Restoration Turns Real in 2014 • Since 2001, Life Extension® has been seeking ways to restore NAD+. • NAD+ is found in young cells and helps guard against degenerative processes. • With age, NAD+ levels plummet. November 2014 https://www.lifeextension.com/magazine/2014/11/the-youth-restoring-benefits-of-nad

111. Life Sustaining Benefits of NAD+

112. At age 50, we have 50% less cellular NAD+ than at age 20. By age 80, NAD+ levels drop 90% and set stage for cellular senescence. NAD+ Levels Plummet with Age September 2017 https://www.lifeextension.com/magazine/2017/9/new-resveratrol-and-nad-dosing-protocol

113. NAD+ May Lengthen Telomeres  “…SIRT1 (NAD+ dependent)) quenches age-related mesenchymal stem cell senescence by mechanisms that include…increased telomerase activity….”1“  Both tankyrases 1 and 2 “(NAD+ dependent) release the inhibitory effect…on telomere elongation.” 2  “Long-term overexpression of tankyrase (NAD+ dependent)…in human cells resulted in a gradual and progressive elongation of telomeres.”3“  Overexpression of tankyrase 1“(NAD+ dependent) in the nucleus promotes telomere elongation…”4 1. “SIRT1 ameliorates age-related senescence of mesenchymal stem cells via modulating telomere shelterin” Front Aging Neurosci. 2014 Jun 3;6:103. doi: 10.3389/fnagi.2014.00103. 2. ”The new life of a centenarian: signaling functions of NAD(P)“ TRENDS in Biochemical Sciences Vol.29 No.3 March 2004 3. “Tankyrase promotes telomere elongation in human cells in human cells”, Current Biology, Volume 10, Issue 20, October 2000 4. “Role for the Related Poly(ADP-Ribose) Polymerases Tankyrase 1 and 2 at Human Telomeres” Molecular and Cellular Biology, , Vol 38, Issue 2 June 2018

114. Senolytics and NAD+ to Reverse Osteoarthritis and Aging  Sirtuin 6 (SIRT6) needed for chondrocyte (cartilage) regeneration.  SIRT6 inactivates with age.  Reactivate SIRT6 with resveratrol and NAD+.  Remove senescent cells with dasatinib plus quercetin. Clinical trials are planned. Self-experimenters may consider this now.

115. How to Boost Cellular NAD+ ►Persons under 50 years supplement with 300-600 mg/day of nicotinamide riboside. ►Older individuals may need NAD+ infusions or patches. ►Follow up NAD+ therapy with 300-600 mg/day of nicotinamide riboside.

116. NAD+ Drug Options Depending on one’s age, the following methods restore NAD+ levels: 400-800 mg of NAD+ patches 3 times/week or two followed by nicotinamide riboside supplementation. 500-750 mg of NAD+ infusions 3 times/week followed by nicotinamide riboside. (Other methods to boost cellular NAD+ being investigated) or

117. NAD+ Patches Dose: 3 patches/week for 1-2 weeks then maintain with 300-1,000 mg/day of nicotinamide riboside NAD+ PATCHES QTY 6 400mg/ml 8 hours $220 QTY 6 800mg/ml 4 hours $316

118. NICOTINAMIDE RIBOSIDE (dietary supplement) Oral ingestion of nicotinamide riboside boosts NAD+ cell levels.

119. Nicotinamide Riboside + Resveratrol $45 per month for 300 mg/day dosing

121. mTOR Inhibition (rapamycin) Step 4:

122. March 28, 2017 “Rapamycin (sirolimus) increased elderly people’s response to flu vaccines by 20%.” This has led to research into whether rapamycin can slow or reverse the symptoms of old age. https://www.technologyreview.com/s/603997/is-this-the-anti-aging-pill-weve-all-been-waiting-for/ “Can a pill make you younger?”

123. Is This the Anti-Aging Pill We’ve All Been Waiting For? A drug derived from an Easter Island bacterium extends the life of lab animals March 28, 2017 https://www.technologyreview.com/s/603997/is-this-the-anti-aging-pill-weve-all-been-waiting-for/

124. March 1, 2018 https://www.the-scientist.com/?articles.view/articleNo/51906/title/Could-Rapamycin-Help-Humans-Live-Longer-/

125. Deadly Impact of Excess mTOR Excess mTOR

126. Excess mTOR and Abdominal Obesity Excess mTOR causes insulin resistance, diabetes, Inflammation and obesity. AMPK activators indirectly suppress mTOR. Rapamycin directly inhibits mTOR pathways.

127. How Does Rapamycin Work? • Directly turns down mTOR • Induces autophagy (rids cells of debris) • Improves bone marrow (immune) function • Decreases excess cell propagation • Metabolizes cellular fat stores • Suppresses toxic senescent cell secretions

128. Mice Treated with Lower-Dose Rapamycin for 90 Days Had 37% Longer Life Expectancy After Treatment 257 188 0 50 100 150 200 250 300 Rapamycin-treated mice Control mice Mean Post-Treatment Life Expectancy (Days) +37% Bitto et al.Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife, 2016;5:e16351.

129. July 13, 2018 Does Rapamycin Slow Down Time? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084391/ Rapamycin is an inhibitor of mTOR and animals treated with it live longer. Rapamycin and other mTOR inhibitors slow biological time by retarding cell proliferation, and retard loss of proliferative potential. Authored by Mikhail V. Blagosklonny

130. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2012.00832.x May 15, 2012 Rapamycin slows aging in mice Rapamycin increases lifespan in mice. This represents an inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging. Many forms of age‐dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as decline in spontaneous activity, occur more slowly in rapamycin‐treated mice. This suggests that rapamycin retards multiple aspects of aging in mice, in addition to beneficial effects it may have on neoplastic (cancer) disease.

131. http://longevityfacts.com/clinical-trial-anti-aging-rapamycin-healthy-seniors/ August 17, 2017 Rapamycin has extended lifespan in every animal tested from yeast to mice. Rapamycin clinical trial moving forward. FDA Approves Clinical Trial of Rapamycin in Healthy Seniors

133. SEPTEMBER 17, 2018 Viewpoint Scientific Discovery and the Future of Medicine “Aging as a Biological Target for Prevention and Therapy” Nir Barzilai, MD1; Ana Maria Cuervo, MD, PhD1; Steve Austad, PhD2 JAMA. Published online September 17, 2018. “The largest overall longevity increase has been found using a combination of rapamycin and metformin…studies suggests that interventions as late as the mouse-equivalent of older than 70 years of age could significantly extend (human) life by more than 20 years and increase health span even more substantially.”

134. Rapamycin Extends Lifespan  Decreased cancer incidence.  Improved cardiac function.  Improved systemic health.  Consistent lifespan increases.* *After brief treatment (mice and dogs). Kaeberlein, Matt. “Translational Geroscience: Targeting mTOR Signaling to Promote Healthy Longevity.” Innovation in Aging, Vol. 1, No. S1 (2017): 743.

135. In elderly mice, 6 weeks of treatment with the mTOR inhibitor rapamycin rejuvenated hematopoietic stem cell function, leading to increased production of naïve lymphocytes, an improved response to influenza vaccination, and extended life span. Rapamycin Increases Production of Naïve Immune Cells & Extends Lifespan “mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells.” Science Signaling 2, ra75 (2009)

137.  Tested 218 people aged 65+ to measure immune response to flu vaccine.  Rapamycin analog (RAD001) used.  Three doses tested (each weekly for 6 weeks): 0.5 mg, 5 mg, and 20 mg.  Subjects received flu vaccine for 3 different flu strains.  Antibody titers measured against a virus protein.  Higher titers representative of stronger vaccine responses.  If antibody titers enhanced more than 20% compared to placebo, for at least 2 of the 3 virus strains, mTOR inhibition considered effective.  Rapamycin analog effective at the doses of 0.5 mg and 5 mg.  High dose of 20 mg may impair vaccine response to 1 strain in some people. 2014, PMID 25540326, doi 10.1126/scitranslmed.3009892 mTOR inhibition improves immune responses in elderly humans

138. “TORC1 inhibition enhances immune function and reduces infections in the elderly” July 11,2018 “The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study (mTOR inhibitor) drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group.” “TORC1 inhibition enhances immune function and reduces infections in the elderly.” Science Translational Medicine-July 11 2018 Elderly people taking mTOR inhibitors had 40% increased response to influenza vaccine.

139. 2018, PMID 29997249, doi: 10.1126/scitranslmed.aaq1564  Two mTOR inhibitors tested: RAD001 + BEZ235.  Response to flu vaccine + number of infections compared to placebo.  Antibody titers 20% higher than placebo considered effective  Improved antibody titers must be observed against all 3 flu strains.  Dose regimen: 0.1 mg/day of RAD001 + 10 mg/day of BEZ235 worked.  People receiving both compounds or BEZ235 alone, reported about 1 fewer infection per year compared to placebo. “TORC1 inhibition enhances immune function and reduces infections in the elderly”

140. Rapamycin and Flu Vaccine Response In Young and Old Mice Reference: Chen, Liu, Liu, Zheng. mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells. Sci Signal. 2009 2(98); ra75. PMID 19934433. doi: 10.1126/scisignal.2000559 Four groups of mice: 1. Young with/without vaccine 2. Young with/vaccine 3. Old + vehicle + vaccine 4. Old + rapamycin + vaccine Four groups of mice: Interventions: 1. 6-weeks rapamycin every other day (or placebo) 2. Injection of vaccine (or not) 3. Injection of flu virus 4. Observe the 4 groups for survival

141. Nine Days after H1N1 Flu Injection: Reference: Chen, Liu, Liu, Zheng. mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells. Sci Signal. 2009 2(98); ra75. PMID 19934433. doi: 10.1126/scisignal.2000559 (Rapamycin restored vaccine response in this study) •Young with no vaccine: 100% dead •Young with vaccine: 100% alive •Old + vaccine (no rapamycin): 65% dead •Old + vaccine + rapamycin: 100% alive

142. Young, no vaccine, 0% Young + vaccine, 100% Old + no rapa, 35% Old + rapa, 100% 0% 20% 40% 60% 80% 100% 120% Surival Effect of rapamycin on vaccine response & infection survival in mice Young, no vaccine Young + vaccine Old + no rapa Old + rapa Reference: Chen, Liu, Liu, Zheng. mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells. Sci Signal. 2009 2(98); ra75. PMID 19934433. doi: 10.1126/scisignal.2000559 Rapamycin-Vaccine Responses & Death Rates

143. GeroScience. 2017 Apr; 39(2): 117–127. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs Silvan R. Urfer, 1,2 Tammi L. Kaeberlein, 1,2 Susan Mailheau, 2 Philip J. Bergman, 3 Kate E. Creevy, 2,4Daniel E. L. Promislow, 1,2,5 and Matt Kaeberlein 1,2 “Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function…in the rapamycin-treated dogs.”

144. Rapamycin Dosage Schedule  Typical dose used by organ transplant patients is around 1 mg a day.  This kind of daily dosing causes side effects.  Dr. Alan Green has developed a protocol using about 6 mg of rapamycin once a week*.  Weekly dosing expected to deliver benefits of mTORC1 inhibition and autophagy without side effects.  Clinical trials to test 6 mg/week of rapamycin and measure aging markers. * Reference for Dr. Green: https://rapamycintherapy.com/

145. Dr. Alan Green at his practice in Little Neck, NY now has 500+ patients using rapamycin with 100+ patient adding dasatinib, fisetin and quercetin . Dr. Green’s Anti-Aging Cocktail 1) Rapamycin 2) Dasatinib 3) Fisetin 4) Quercetin Now in Clinical Use: https://senolyticstreatment.com/

146. Caveats Regarding mTOR Suppression • Do not excessively suppress mTOR as this can contribute to sarcopenia, frailty and excess weight loss. • Some people aggressively suppress mTOR for 3 months and then eat normally for 1 month. During this period they usually reduce or discontinue AMPK activators. • Any intervention carries inherent risk of iatrogenesis, which describes adverse events related to medical treatment. Letting aging take its normal course is itself inevitably risky

147. Best Brand of Rapamycin Dosage: 6 mg one time weekly 3 x 2 mg tablets of Rapamune® = 6 mg Local pharmacy price: $2,600 (100 2 mg tabs) Costs about $300 a month. Lower prices available online but insist on: Rapamune® for now

148. Tailormade Compounding 200 Moore Drive Nicholasville, KY 40356, United States P : 1 (859) 887 0013 F : 1 (859) 406 1242 https://tailormadecompounding.c om/contact-us/ Compounded Sirolimus 3 mg (two tablets once a week) Generic Two 3 mg tablets cost $18 a week or $936 per year

149. age-reversal.net To find out about additional sources for experimental therapies:

150. 2021 2030

151. PNAS October 15, 2019 116 (42) 20817-20819; first published September 30, 2019 https://doi.org/10.1073/pnas.1913212116 Rapamycin1 ** Lithium Senolytic2 + + Fruit Fly Lifespan Extension by 48%3 = This recent study supports a scientific approach to enable longer lifespans. September 30, 2019 1) Rapamcyin benefits can partially occur when AMPK is activated. 2) Health-conscious people today are utilizing senolytics. 3) Humans require multi-model therapies to achieve lifespan extension

152. Rapamycin Reverses Heart Dysfunction Late-life mice treated with rapamycin for 3 months showed:  Significant benefits in cardiovascular function with reversal or attenuation of age-related changes in the heart.  Beneficial behavioral, skeletal, and motor changes compared with mice fed a control diet.  Reduced indicators of inflammatory, metabolic, and hypertrophic expression in cardiac tissues. “From these findings, we propose that late- life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues…” Aging Cell. 2013 Oct;12(5):851-62. doi: 10.1111/acel.12109. Epub 2013 Jul 7. Late-life rapamycin treatment reverses age-related heart dysfunction.

153. NIH Funds $23 Million Dog Study that includes RAPAMYCIN Daniel Promislow principal investigator of the Dog Aging Project “Old dogs, new tricks: 10,000 pets needed for aging study” https://www.nbcnews.com/health/health-news/old-dogs-new-tricks-10-000-pets-needed-science-n1082151

154. https://clinicaltrials.gov/ct2/show/NCT04488601 Rapamycin Human Study Receives $183,000 Funding  Randomized, placebo-controlled trial into the safety/efficacy of rapamycin in reducing clinical measures of aging in an older adult population.  Four differing rapamycin doses and dosing schedules evaluated.  Primary Outcome Measure: Changes in visceral fat as measured by (DXA) scan.  Secondary Outcomes: Range of clinical measures, e.g. bone density, blood tests, etc.  Estimated study start date: . Sponsor: AgelessRx Collaborator: University of California, Los Angeles Principal investigators: James Watson, M.D. and Sajad Zalzala, M.D. June 18, 2021

155. Rapamycin Extends Lifespan • Brief treatment in middle-aged mice & dogs increases lifespan by over 50%. • Improved health across wide range of markers. • Rapamycin associated with decrease in cancer incidence and improvement in cardiac function.

156. Unified Theory of Stem Cell Rejuvenation • Adult stem cells lose ability to repopulate tissues with functional cells. • Systemic deterioration occurs as functional cells degenerate/die. • How your stem cells may be renewed: Published overview: 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 •Remove senescent cells

159. Biologics(exosomes,perinataltissues,hGH) Step 5:

160. Bone Marrow Yields Regenerative Stem Cells Bone + Bone Marrow

161. “By splicing animals together, scientists have shown that young blood rejuvenates old tissues. Now, they are testing whether it works for humans.” January 21, 2015 January 21, 2015

162. University of Cambridge and Harvard researchers show that young blood promotes repair of damaged spinal cords in older mice.1 Harvard neuroscientist finds that young blood sparks the formation of new neurons in the brain and olfactory system.2 Brigham and Women's Hospital in Boston, Massachusetts — cardiologists find that young blood reverses age-related thickening of the walls of the heart.3 1)Ruckh, J. M. et al. Cell Stem Cell, 10, 96–103 (2012). 2)Katsimpardi, L. et al. Science, 344, 630–634 (2014). 3) Loffredo, F. S. et al. Cell, 153, 828–839 (2013).

163. Young Blood Transfer Research goes Mainstream Johnson and Johnson signs $50 million deal with Stanford University researchers to identify blood factors responsible for age reversal in parabiosis studies: "…it could mean new therapeutic approaches for treating numerous diseases associated with aging, including neural dysfunction and dementias such as Alzheimer's disease.” March 4, 2015

164. Scientists have rejuvenated old mice with the blood of human teenagers The fountain of youth is real, and it's creepy. PETER DOCKRILL 16 NOV 2016 Nov 16 2016

165. •Improved cognition •Decreased inflammation •New brain cell formation •Old animals acted young Society of Neuroscience annual meeting-San Diego- Nov 2016 Small amounts of young human plasma injected into old mice:

166. 168 “The new blood made the old mice act young again, with the treated animals running around in open spaces much like their younger controls.” Nov 16 2016

167. March 22, 2017 Mice treated with young human plasma appeared to have created more new cells in their brain. “Young human plasma treatment can increase neurogenesis.” Growing New Brain Cells

168. Parabiosis Extends Longevity • University of California researchers studied the life spans of old–young rat pairs in 1972. • Old rats receiving young circulating blood lived the human equivalent of 10-12 years longer. Source: New York Academy of Sciences, (1972 Nov) Vol. 34, No. 7, pp. 582-7.

169. “Young bone marrow transplantation preserves learning and memory in old mice”, Communications Biology (2019). DOI: 10.1038/s42003-019-0298-5 “Young bone marrow rejuvenates aging mouse brains, study finds” Transplanting the of young mice into old mice prevented cognitive decline in the old mice. Available at:https://medicalxpress.com/news/2019-02-young-bone-marrow-rejuvenates-aging.html. February 20, 2019

170. “Young bone marrow rejuvenates aging mouse brains, study finds” Microglia in brains of old mice have fewer/shorter branches than young mice Available at: https://medicalxpress.com/news/2019-02-young-bone-marrow-rejuvenates-aging.html. Feb. 20, 2019 Synaptic branches of microglia of old mice who received bone marrow transplants from young mice resembled those of young mice

171. Young Bone marrow transplants restore exploratory activity in old mice Feb. 20, 2019 “Remarkably, young bone marrow recipients, but not old bone marrow recipients, were more active than old control mice.” https://www.nature.com/articles/s42003-019-0298-5/figures/1

172. “Young bone marrow rejuvenates aging mouse brains, study finds” Available at: https://medicalxpress.com/news/2019-02-young-bone-marrow-rejuvenates-aging.html. Feb. 20, 2019 Young bone marrow restores aged mouse brains!

173. PHILADELPHIA (CBS) — Could the secret to eternal youth be found in blood transfusions from young people? Some claim that transfusions with “young blood” from teenagers can reverse the aging process. Dec. 20, 2018 Controversial Treatment Transfuses Patients With ‘Young Blood’From Teenagers To Reverse Aging Process

174. Stanford University scientists previously showed that transfused serum from 12-to-15-month age mice into old mice reverses some signs of brain aging. Kathlyn J. Gan et al. Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1902672116 JUNE 3, 2019

175. Researchers find synapse-boosting factors in young blood Available at: https://medicalxpress.com/news/2019-06-synapse-boosting-factors-young-blood.html. Accessed June 4, 2019. June 4, 2019 Stanford University researchers used serum from 15-day old (very young) mice and discovered: “ ”

176. https://medicalxpress.com/news/2019-06-synapse-boosting-factors-young-blood.html 15-Day old Mouse (left) compared to 15-Month Old Mouse (right)

177. Very Young Blood (serum) Regenerates Synapses, Dendrites, Neurotransmitters Available at: medicalxpress.com/news/2019-06-synapse-boosting-factors-young-blood.html. Accessed June 4, 2019. June 4, 2019 “When two proteins (thrombospondin-4 and SPARC-like protein-1) richer in younger serum were applied to older serum…some of the same rejuvenating effects took place.”

178. “Strikingly, recombinant THBS4 and SPARCL1… may represent rejuvenation factors that enhance synaptic connectivity by increasing dendritic arborization, synapse formation, and synaptic transmission.” Kathlyn J. Gan et al. Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1902672116 JUNE 3, 2019 Human equivalent of a 15-day old mouse may be approximately one to two years.

179. 318% increased value in five years September 7, 2020 Remaining stake in young plasma group Alkahest sells for $146 million  Alkahest develops treatments forage-related diseases.  Therapies target the aging plasma proteome.  Company has four candidates in six phase-2 clinical trials.  Founded byStanfordUniversityscientists who demonstrated youngbloodfactors restoremental capabilities in old animals. https://www.pharmaceutical-business-review.com/news/grifols-alkahest-full-ownership/ “Now we see a wealth of plasma-derived and non-plasma therapeutic candidates identified by Alkahest that can significantly support the unmet needs of many diseases associated with aging.”

180. What is Epigenetic Age? “Epigenetics” refers to external modifications that occur in gene expression as a result of what we do to our bodies, as opposed to the genetic code we are born with. Ingesting overcooked food or inhaling cigarette smoke causes deleterious epigenetic changes to DNA. Vitamin D and omega-3s induce beneficial epigenetic effects. Examples:

181. DNA methylation controls the transcription (activation) of genes. Without proper DNAmethylation, beneficial genes are deactivated while harmful genes can be over-expressed. DNA Methylation measures Epigenetic Age Young plasma treatment more than halved epigenetic ages. This is the principal of what is called “epigenetic aging.”

182. April 21st, 2020 Horvath, S., Singh, K., Raj, K., Khairnar, S., Sanghavi, A., Shrivastava, A., ... & Lehmann, M. (2020). Reversing age: dual species measurement of epigenetic age with a single clock. bioRxiv. Young plasma treatment more than halved the epigenetic ages of blood, heart and liver tissues. Epigenetic clock measures indicate systemic rejuvenation.

183. https://www.biorxiv.org/content/10.1101/2020.05.07.082917v1.full April 21st, 2020 Cellular senescence reduced in vital organs. Young Plasma fraction improvesorganfunctionand measures of cognition. The effect of plasma fraction treatment on cellular senescence: After a 155-day treatment period, the brains of young plasma treated old rats and young rats were stained for senescence- associated “beta- galactosidase”, whose activity on the substrate turns senescent cells blue in color.

184. Within 10 days of young plasma fraction treatment the physical capacities of old rats are indistinguishable from that of the young rats. Horvath, S., Singh, K., Raj, K., Khairnar, S., Sanghavi, A., Shrivastava, A., ... & Lehmann, M. (2020). Reversing age: dual species measurement of epigenetic age with a single clock. bioRxiv. Grip Strength Analysis April 21, 2020

185. Rejuvenation of Three Germ Layer TissuesbyRemovingOldBloodPlasma May30,2020 https://www.aging-us.com/article/103418/text Result likely due to the removal of extra-cellular “junk” in old plasma. Removal of 50% of an aged mouse’s plasma and replacing it with saline containing 5% albumin resulted in enhanced muscle repair, reduced liver fat and fibrosis, and increased neurogenesis.

186. July 10th, 2020 Blood Factors Transfer Beneficial Effects of Exercise on Neurogenesis and Cognition to the Aged Brain Researchers transfused plasma from old mice who were allowed to exercise for 6 weeks to other old mice who were not allowed. Rodents who received the plasma from the active mice grew roughly twice as many new neurons in the hippocampus as controls. https://www.sciencemag.org/news/2020/07/protein-blood-exercising-mice-rejuvenates-brains-couch-potato-mice Couch potato mice receiving this blood eight times over 3 weeks did nearly as well onlearning and memory tests as the exercising mice.

187. “...aged mice that received plasma from middle-age or old mice that exercised showed beneficial effects in their brains without hitting the treadmill.” https://science.sciencemag.org/content/369/6500/167 An enzyme generated in livers of exercising mice demonstrate similar brain restoring effects. Blood factors transfer beneficial effects of exercise to the aged brain

188. https://www.magentatx.com/revolutionizing-medicine/programs/ Immune reset throughtransplant: a2-step process Step 1: Remove the disease-causing cells Step 2: Replace with healthy cells to rebuild immune system. Three new agents — CD45-ADC, CD117-ADC, and C300 — precisely remove only disease-causing cells in the body, without the need for chemotherapy or radiation, and make room for incoming healthy cells to rebuild a functioning immune system. Rebuild Bone Marrow to Restore Youthful Immunity

189. RestoringYouthfulImmunitybyRebuildingBoneMarrow https://www.magentatx.com/revolutionizing-medicine/programs/

190. LifeExtension.com

191. Oct.14,2017 Cardiac and Systemic Rejuvenation after Cardiosphere Derived (Progenitor) Cell Therapy in Senescent Rats Aging is characterized by progressive shortening of telomeres and is associated with heart dysfunction and reduced regenerative capacity. CDCs also work indirectly to reverse aging systemically… https://academic.oup.com/eurheartj/article/38/39/2957/4080843 1) Cardiomyocytes 2) Endothelial cells 3) Smooth muscle cells Cardiosphere-derivedcells(CDCs)are cardiacprogenitorcells thatcandifferentiateintothethreemajorheartcelltypes:

192. October14,2017 Effects of Cardiosphere-derived Cells in Old Hearts Young rat CDCs transplanted into hearts of old rats resulted in: https://academic.oup.com/eurheartj/article/38/39/2957/4080843 Restored young gene expression pattern in heart cells of old animals (in 85.5% of genes). Telomeres in heart cells were longer with hypertrophy and myocardial fibrosis reduced. Improved diastolic dysfunction and lowered a heart failure marker (natriuretic peptide).

193. October14,2017 In Vivo Effects of Cardiosphere-derived Cells Young CDCs transplanted into hearts of old rats resulted in: https://academic.oup.com/eurheartj/article/38/39/2957/4080843 Exercise capacity increased 20% Body weight decreased 30% Hair regrowth after shaving more robust Inflammatory markers reduced 25%-60% Senescent cell population reduced

194. Bridging the Longevity Gap Urgent Need to Access Age-Reversal Interventions

195. March 2002

197. Risk of Delaying Human Research Chronic Diseases May Negate Regenerative Benefits

198. 2020 2030

199. Adult stem cells lose ability to repopulate tissues with functional cells. Systemic deterioration occurs as functional cells degenerate. 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  Remove senescent cells How your stem cells may be renewed:

200. Boost cellular AMPK Reduce senescent cells Replenish NAD+ Suppress excess mTOR Express sirtuins metformin (1000-2000 mg daily) dasatinib/quercetin/fisetin infusions, patches, precursors rapamycin (6 mg once week) resveratrol, pterostilbene Summary of Experimental Interventions Advance to “biologics”, i.e., exosomes, perinatal tissues, growth hormone, et al.

205. For free subscription to Life Extension Magazine log on to: DMook@LifeExtension.com

206. Unparalleled Track Record of Biomedical Innovation Established 1977

207. age-reversal.net This entire presentation and info about our research available at:

Unified Theory of Stem Cell Rejuvenation

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