Unified Theory of Stem Cell Rejuvenation

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

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

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)

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)

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

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:

“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

“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

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

 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:

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

“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.

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;

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

AMPK Activation (metformin)
Step 1:

“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.

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.”

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

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)

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

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.

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

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:

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:

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)

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.

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%

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

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/

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.”

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

 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.

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 …

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 …

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 …

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
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
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.

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 …

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
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 …

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 …
10.2174/0929867324666170718110606.PMID: 28721827 Review.
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 …
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 …

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 …
10.2174/0929867324666170718110606.PMID: 28721827 Review.
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 …
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 …

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

Reducesenescentcells(senolytics)
Step 2:

Senolytics are compounds
that selectively destroy
senescent cells.

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

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.

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:

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.

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
Untreated Senolytic Treated Starting at Mid-Age

Improved organ function when
senescent cells are removed
Bent spine
Cataract
Same age mouse
looks much younger
Hair loss
Normal Age Same Age / Senolytic Treated
 Improved kidney function.
 Hearts more resilient to stress.
 Extended lifespans.

Lifespan Increase in Senolytic-Treated Mice
Median lifespans increased 24% to 27%
Bent spine
Cataract
Same age mouse
looks much younger
Hair loss
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

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.”

SEPTEMBER 17, 2018
Scientific Discovery and the Future of Medicine
“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.”

“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…”

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/

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.

Deadly Impact of Senescent Cells
July 9, 2018
“This indicates potency of senescent cells in shortening healthspan/lifespan.”
Transplanting senescent
cells into older mice causes:
1) Degenerative pathologies
2) Reduced survival

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

Senolytics Increase Lifespan in Old Age
July 9, 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.”

“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…

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

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

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.”

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.”

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/

 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

“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

“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.”

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

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

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.

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.

“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

“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."

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)

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

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)

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.

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.

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

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/

Senolytic Activator with Bio-Fisetin

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:

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/

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

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

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

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/

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?)

Sharp Drop in NAD+ Tissue Levels with Age

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

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

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

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

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.)

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

 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

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

Life Sustaining Benefits of NAD+

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

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

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.

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.

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

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

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

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

mTOR Inhibition (rapamycin)
Step 4:

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?”

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/

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

Deadly Impact of Excess mTOR
Excess
mTOR

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

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

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.

July 13, 2018
Does Rapamycin Slow Down Time?
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

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.

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

SEPTEMBER 17, 2018
Viewpoint
“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.”

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.

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)

 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

“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.

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”

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

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

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

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.”

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/

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

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

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

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

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

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.

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

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

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.

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

Biologics(exosomes,perinataltissues,hGH)
Step 5:

Bone Marrow Yields Regenerative Stem Cells
Bone + Bone Marrow

“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

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).

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

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

•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:

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

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

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.

“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

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

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

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

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

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

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:
“ ”

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

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.”

“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.

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.”

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:

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.”

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.

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.

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

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.

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.

“...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

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

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

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:

October14,2017
Effects of Cardiosphere-derived Cells in Old Hearts
Young rat CDCs transplanted into hearts of old rats resulted in:
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).

October14,2017
In Vivo Effects of Cardiosphere-derived Cells
Young CDCs transplanted into hearts of old rats resulted in:
Exercise capacity increased 20%
Body weight decreased 30%
Hair regrowth after shaving more robust
Inflammatory markers reduced 25%-60%
Senescent cell population reduced

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

Risk of Delaying Human Research
Chronic Diseases May Negate Regenerative Benefits

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:

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.

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Unified Theory of Stem Cell Rejuvenation

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