Bill Faloon's Keynote Presentation at RAADfest 2024

In his keynote presentation at RAADfest 2024, Bill Faloon gives a research update on recent advances in life-extension and age-reversal research. Topics explored included IL-11, young plasma transfer, exosomes, cellular reprogramming with Yamanaka factors, gene editing, epigenetic age reversal, and FDA regulation.

1. Age Reversal Advances from Cells to Mice, Monkeys and Humans  RAADfest 2024 – Anaheim, CA Sept 5 th , 2024 Bill Faloon Life Extension®

2. Prospect of Human Age Reversal William Faloon

3. Human AgE Reversal The New Paradigm A BIOMEDICAL Renaissance!

4. April 27, 2019 “Anti-aging drugs are coming that could keep you healthier for longer” https://www.newscientist.com/issue/3227/

5. March 7, 2022 https://www.webmd.com/healthy-aging/story/is-there-a-cure-for-aging Feb. 20, 2021 “Is There a Cure for Aging?” “Fueled in part by a billion dollars of investor money, they are attempting to reverse- engineer your molecular biological clock. To eliminate not merely diseases that kill people, but to prevent death itself .”  Their Goal?

6. “Scientists safely and effectively reverse the aging process in middle-aged and elderly mice by partially resetting their cells to more youthful states.” https://www.salk.edu/news-release/cellular-rejuvenation-therapy-safely-reverses-signs-of-aging-in-mice March 7, 2022 Salk Scientists Reverse Aging in Mice

7. 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 .”

8. Decades Ahead of Mainstream Medicine Track Record Available at: https://www.lifeextension.com/about/life-extension-story/history 1981 DHEA to delay systemic aging 1985 1986 1992 Aspirin to prevent heart attack CoQ10 to reverse heart failure Lycopene to reduce cancer risk Cimetidine as adjuvant cancer therapy Melatonin to improve immune function 1983 First to introduce:

9. August 2 nd , 2023 “There's one major key to unlocking extreme longevity.” “If humans living for 1,000 years seems like a complete stretch, aging expert João Pedro de Magalhães will do you one better: how about humans living for 20,000 years ?” https://www.popularmechanics.com/science/health/a44713943/humans-can-live-20000-years-aging-expert/ “An Aging Expert Thinks Humans Can Live for 20,000 Years. He's Not Crazy.”

10. The Economist Dedicates an Entire Issue to Age Reversal https://www.economist.com/technology-quarterly/ 2023-09-30 Sept 30, 2023

11. https://www.webmd.com/healthy-aging/story/is-there-a-cure-for-aging February 20, 2021

12. June 12, 2018 Bill Faloon has pursued immortality for decades. Now he's got lots of company. What does science have to say? The Man https://www.popsci.com/forever-man-immortality-science/ June 12, 2018

13. December 17, 1903 First flight: 120 feet/20 feet off ground

14. December 17, 1903 International Headline News

15. December 20, 1957 Intercontinental Air Travel 54 Years after Wright Brothers first-in flight

16. April 9 th , 2021 https://www.wsj.com/articles/nasas-ingenuity-mars-helicopter-gets-set-for-historic-first-flight-on-another-world-11617465600 |

17. 1903 2021 Exponential Advances in only 118 Years Wright Brother’s First Flight Helicopter Flies on Mars

18. 8,000 B.C. – 1899 A.D. 1900 – 2024 A.D. Time in Perspective (Recorded Human History) More progress has occurred since 1900 than prior 8,000 years of human history.

19. https://www.technologyreview.com/magazine/2019/09 September 2019 “…at a conference of longevity enthusiasts called RAADfest … Bill Faloon plans to take the strategy one step further with what he has been calling the “Perpetual Clinical Trial.” “OLD AGE IS OVER!”

20. Unparalleled Track Record of Biomedical Innovation First Established 1977

21. Sept. 11, 2023 National Geographic Issue: “The Science of Longevity” National Geographic echoes what has been presented at longevity seminars for decades.

22. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2820220 June 20, 2024 “Healthy Lifestyle and the Likelihood of Becoming a Centenarian” JAMA Network Open.  2024;7(6):e2417931. doi:10.1001/jamanetworkopen.2024.17931 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2820220   “Even when a healthier lifestyle is initiated at age 80 or older, people with the healthiest lifestyle scores improved their odds of reaching centenarian status by 61% in comparison with those with the lowest scores.” Healthier Lifestyles Improve Odds of Living to 100 Years

23. July 17th, 2024 https://www.bbc.com/news/articles/cv2gr3x3xkno These mice are the same age! The one on the right given an IL-11 inhibitor . “A drug has increased the lifespans of laboratory animals by nearly 25% , in a discovery scientists hope can slow human aging too.”

24. IL-11 inhibition extends lifespan by 22-25% in mice IL-11 involved in inflammation- fibrosis . IL-11 increases with age. IL-11 inhibition extended lifespan in male and female mice Effective in young and older mice Survival curves note that 40-50% of the treated mice alive at study compared to 10% of controls. https://www.nature.com/articles/s41586-024-07701-9 Study published in Nature on July 17 th , 2024 22.5% Lifespan Boost 25% Lifespan Boost

25. Normal Aged Mice without IL-11 inhibition therapy

26. Gene-Altered Mice Unable to make Interleukin-11 These mice lived 22-25% longer.

27. What did IL-11 inhibition accomplish? https://www.nature.com/articles/s41586-024-07701-9 Researchers reported effects seen from other life-extending interventions: Inhibition of mTORC1 Increased AMPK activity Reduced markers of senescence (p16 & p21) Decreased liver fibrosis Upregulated brown adipose tissue Reduced fat mass, cholesterol, & triglycerides Improved insulin sensitivity

28. Researchers tried two methods of inhibiting IL-11: Knockout IL-11 gene from birth (life-long inhibition) Extended median lifespan by about 25% Degree of maximum lifespan extension might be even larger (40-50% of treated mice are still alive vs. 10% of control mice) Result: Method 1: nature https://www.nature.com/articles/s41586-024-07701-9

29. Administer anti-IL-11 antibody at age 75 weeks (older mice) Extended median lifespan by about 23% Degree of maximum lifespan extension might be even larger ( 40-50% of treated mice are still alive vs. 10% of control mice) Result: Method 2: nature https://www.nature.com/articles/s41586-024-07701-9 Note:

30. It is estimated that 45% of deaths in the industrialized world are related to fibrosis . https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/fibrosis Fibrosis  is the replacement of functional tissue with excess fibrous connective tissue, leading to a reduction in organ function and ultimately organ failure/death

31. 2. LASN01 Several anti-IL-11 drugs are in development, targeting the interleukin-11 pathway to treat various fibrotic diseases: 3. BI 765423 by Boehringer Ingelheim: This first-in-class IL-11 inhibitor antibody has entered clinical development, with a Phase 1 study assessing its safety, tolerability, and pharmacokinetics in healthy volunteers. This drug is part of a broader effort to combat fibrotic diseases across various organs. by Lassen Therapeutics: This is another monoclonal antibody, but it specifically targets the IL-11 receptor (IL-11R). It's also in Phase 1 clinical trials, with a focus on its potential to treat fibrotic diseases by blocking the critical pathways that lead to tissue scarring. 1. 9MW3811 by Mabwell Therapeutics: This monoclonal antibody targets interleukin-11 and is currently being tested in a Phase 1 clinical trial in Australia. It is being developed for the treatment of idiopathic pulmonary fibrosis and certain cancers, exploring its potential to inhibit fibrosis and inflammation. We will advise members when these drugs become available: age-reversal.net

32. https://pubmed.ncbi.nlm.nih.gov/11172736/ https://www.nature.com/articles/s41591-021-01536-x https://pubmed.ncbi.nlm.nih.gov/34077894/  1. Lutein Preclinical findings suggest that IL-11 may be reduced by: 2. Resveratrol https://pubmed.ncbi.nlm.nih.gov/37480086/   3. Curcumin or beta blocker (timolol) Methods to Suppress IL-11?

33. IL-11 Inhibited Mice Same-Age Control Mice

34. The Economist Dedicates an Entire Issue to Age Reversal https://www.economist.com/technology-quarterly/ 2023-09-30 Sept 30, 2023

35. https://www.economist.com/technology-quarterly/2023/09/25/slowing-human-ageing-is-now-the-subject-of-serious-research https://www.economist.com/technology-quarterly/2023/09/25/some-claim-human-lifespans-can-be-lengthened-indefinitely

36. https://www.economist.com/technology-quarterly/2023/09/25/what-the-young-can-give-to-the-old https://www.economist.com/technology-quarterly/2023/09/25/ageing-bodies-need-to-get-rid-of-decrepit-cells

37. https://www.economist.com/technology-quarterly/2023/09/25/fighting-ageing-requires-properly-equipped-cells https://www.economist.com/technology-quarterly/2023/09/25/eating-fewer-calories-can-ward-off-ageing

38. Bloomberg Businessweek runs “T he Longevity Issue” https://www.bloomberg.com/features/2023-longevity-issue/ “Do you want to live longer? Live better? Live forever ? Humanity’s obsession with the fountain of youth never gets old, truly. Only now there’s actual science , not just pure science fiction—and also millions of dollars dedicated to this immortality -obsessed frontier.” THE LONGEVITY ISSUE Businessweek December 20 th , 2023 |

39. George Church https://www.52-insights.com/interview-george-church-playing-god-with-our-genes-science/ May 4, 2018 We’ve been doing aging reversal on a variety of different traits — cardiac disease, kidney, obesity, diabetes…and we have examples of gene therapies that can affect all of these simultaneously.” Playing God With Our Genes

40. | December 8 th , 2023 https://www.wsj.com/tech/biotech/fda-approves-worlds-first-crispr-gene-editing-drug-for-sickle-cell-disease-8c65fbb3 Front Page of WSJ: “The gene-editing revolution is jumping from the lab to the marketplace. The U.S. has approved the world’s first medicine employing CRISPR technology.

41. January 16 th , 2024 “FDA clears first CRISPR treatment for a second disease, beta thalassemia” Stem cells genetically modified using CRISPR/Cas9 gene editing. www.cnn.com/2024/01/16/health/crispr-casgevy-beta-thalassemia Modified cells transplanted back into body, where they multiply & increase hemoglobin production.

42. | March 11 th , 2024 https://www.wsj.com/health/pharma/doctors-can-now-edit-the-genes-inside-your-body-4c8e1aea Front Page of WSJ: “The experimental therapies Odunsi and others are receiving, by contrast, edit their cells inside their bodies. “In vivo” gene editing, as the approach is called, could transform medicine.

43. z “Welcoming the Era of Gene Editing in Medicine” https://www.nejm.org/doi/full/10.1056/NEJMp2314279 April 24 th , 2024 “Given the speed of innovation and momentum from recent success, I believe efficient systemic delivery of gene-editing cargo will inevitably make its way from bench to bedside, ultimately making gene editing an equitable, accessible treatment method.” George Q. Daly, MD, PhD Dean of Harvard Medical School :

44. Feb 12, 2024 Hevolution Announces $115 Million Grants Program https://longevity.technology/news/hevolution-announces-49-awards-in-115m-grants-program/ “ Hevolution will invest up to $115 million in this first cohort of 49 selected projects over the next 5 years.” “ Hevolution also plans to announce a second call for proposals later this year , offering an additional $115 million to address the significant funding gaps in aging research .”

45. May 28th, 2024 Turn Bio inks $300 million epigenetic reprogramming deal… https://longevity.technology/news/turn-bio-inks-300m-epigenetic-reprogramming-deal-with-hanall-biopharma/ “The collaboration aims to develop multiple epigenetic reprogramming treatments for age-related eye and ear conditions… Turn Bio’s epigenetic reprogramming technology seeks to restore optimal gene expression and promote tissue regeneration by addressing aging effects in the epigenome... Turn Bio co-founder Vittorio Sebastiano said the power of the company’s technology is its ability to ‘ rejuvenate cells in virtually any organ in the body .”

46. Epigenetic age is a biomarker associated with age-related disease and all-cause mortality.  Epigenetic age is measured by a composite of cell DNA methylation (DNAm) levels. Epigenetic age is considered most accurate way of assessing whether individuals are aging faster or slower than their chronological age. Younger epigenetic age is found among long-lived individuals.  Older epigenetic age is associated with lower levels of physical/ cognitive functions  and reduced longevity . July 27 th , 2022 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331104/ What is Epigenetic Age?

47. What Happened in early 2024 OSK transcription factors reversed epigenetic age, improved overall health and extended remaining lifespans >100% in old rats…research advancing to old monkeys . Exosome-rich young plasma cut old rat epigenetic ages in half and improved overall health…research now advancing to dogs . Next steps: Replicate these findings in murine models while simultaneously initiating OSK and young plasma research in old primates . Young plasma reversed epigenetic aging in old rats and increased median lifespan human equivalent of about 7 years . 1) 2) 3 )

48. This dosing regimen is practical for humans & a primate study is being designed using same exosome-rich young plasma fraction . “Cuts old age in half” https://link.springer.com/article/10.1007/s11357-023-00980-6/ February 2024 Intriguing dosing schedule: Exosome-rich young plasma fraction infused IV (tail) every other day for 8 days. 95 days later repeat once Exosome-Rich Young Plasma Fraction Treatment Protocol

49. Plasma Fraction Reverses Epigenetic Age Liver: 74.6% Blood: 64.3% Heart: 46.5% Brain: 24.4% (h ypothalamus ) February, 2024 Refined Exosome Concentrate Horvath, S., Singh, K., Raj, K. et al. Reversal of biological age in multiple rat organs by young porcine plasma fraction. GeroScience 46, 367–394 (2024). https://doi.org/10.1007/s11357-023-00980-6 Average DNAm age reduced as much as 67.4% Two-year-old rats (circa 60 -year-old human age) treated with “ exosome fraction of plasma ” from young adult pigs reduced epigenetic age by:

50. https://link.springer.com/article/10.1007/s11357-023-00980-6/figures/2 February 2024 Robust Age Reduction measured by DNAmAge in Tissues Tissue Epigenetic Age of Old Control Rat Tissue Epigenetic Age of Young Control Rat Tissue Epigenetic Age of Old Rat Given Young Plasma

51. https://link.springer.com/article/10.1007/s11357-023-00980-6/figures/2 February 2024 Robust Age Reduction measured by DNAmAge Human-Rat Tissue Tissue Epigenetic Age of Old Control Rat Tissue Epigenetic Age of Young Control Rat Tissue Epigenetic Age of Old Rat Given Young Plasma

52. Liver Function Markers Restored to Youthful Ranges https://link.springer.com/article/10.1007/s11357-023-00980-6/figures/3 February 2024 Liver Function Biomarker of Old Control Rat Liver Function Biomarker of Young Control Rat Liver Function Biomarker of Old Rat Given Young Plasma

53. Reversal of Conventional Measures of Cardiovascular Risks https://link.springer.com/article/10.1007/s11357-023-00980-6/figures/3 February 2024 Cardiovascular Function Biomarker of Old Control Rat Cardiovascular Function Biomarker of Young Control Rat Cardiovascular Function Biomarker of Old Rat Given Young Plasma

54. Restoration of Youthful Kidney Function Markers https://link.springer.com/article/10.1007/s11357-023-00980-6/figures/3 February 2024 Note creatinine levels returned to young, healthy ranges 150 days posttreatment. This indicates potential of reversing chronic kidney disease . Kidney Function Biomarker of Old Control Rat Kidney Function Biomarker of Young Control Rat Kidney Function Biomarker of Old Rat Given Young Plasma

55. Beneficial Reductions in Epigenetic Age https://link.springer.com/article/10.1007/s11357-023-00980-6 February 2024 In young plasma-treated old rats, epigenetic ages of blood, liver, and heart reduced to levels… “comparable with young rats.”

56. Mesenchymal stem cell-derived exosomes promote tissue repair . Hematopoietic stem cell-derived exosomes can improve immunity and blood cell production while lowering inflammation . Exosomes are secreted by cells and play crucial roles in communication and nutrient transport between cells Mesenchymal stem cell-derived exosomes promote tissue repair. Stem cell -derived exosomes have potential regenerative therapeutic applications.

57. Young pig plasma ( E5 ) was formulated with super high levels of exosomes compared to umbilical cord or young plasma. Translating Young Plasma Findings into Clinical Practice In the young pig plasma study, researchers calculated the normal amounts of exosomes in the rat's bloodstream and then gave them enough E5 to equal that amount daily, for four days (every other day over an eight-day period).   In an umbilical cord plasma concentrate study, we probably gave a few hundred million exosomes to each patient once a week…with lackluster results . For a 150-pound person, this might equate to 4.82 trillion exosomes a day .

58. Published Reports Describing Regenerative Potential of Young Plasma Preclinical Assessment of Young Blood Plasma for Alzheimer Disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172595/ The Plasma for Alzheimer Symptom Amelioration (PLASMA) Study https://clinicaltrials.gov/study/NCT02256306 A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984263/ The Stanford Parkinson's Disease Plasma Study https://clinicaltrials.gov/study/NCT02968433

59. Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439869/    Preclinical Assessment of Young Blood Plasma for Alzheimer Disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172595/        Young Blood Plasma Administration to Fight Alzheimer's Disease? https://www.liebertpub.com/doi/10.1089/rej.2017.1940     Platelet factors attenuate inflammation and rescue cognition in ageing https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468395/ Young blood plasma reduces Alzheimer's disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278124/  Plasma-Based Strategies for Therapeutic Modulation of Brain Aging https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694331/   Young Plasma Studies Continued…

60. Young Plasma Studies Continued… Aging and age-related diseases with a focus on therapeutic potentials of young blood/plasma https://link.springer.com/article/10.1007/s00210-023-02657-5     Circulating plasma factors involved in rejuvenation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746393/     Plasma from Young Rats Injected into Old Rats Induce Antiaging Effects https://www.liebertpub.com/doi/10.1089/rej.2020.2354      The effect of aging on the bone healing properties of blood plasma https://www.injuryjournal.com/article/S0020-1383(21)00426-5/fulltext      Young plasma ameliorates aging-related acute brain injury after intracerebral hemorrhage https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522807/      Undulating changes in human plasma proteome profiles across the lifespan https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062043/     Young Plasma Rejuvenates Blood Dna Methylation Profile, Extends Mean Lifespan And Improves Physical Appearance In Old Rats https://pubmed.ncbi.nlm.nih.gov/38430547/

61. Young Plasma Rejuvenates Blood Dna Methylation Profile, Extends Mean Lifespan And Improves Physical Appearance In Old Rats  https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/glae071/7618060 “We conclude that young plasma therapy may constitute a natural noninvasive intervention for epigenetic rejuvenation and health enhancement.” March 2, 2024 March 2, 2024 March 2, 2024

62. https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/glae071/7618060 May 2024 The Journals of Gerontology This study partially funded by the Life Extension® group “This study was supported in part by a research grant from the Healthy Life Extension Society, Belgium and from research grant Grant # SEGR-9-23-21 from the Society for Experimental Gerontological Research to R.G.G., and grant PICT 2018-2446 to C.B.H. S.H. was supported by the Paul G. Allen Frontiers Group” Funding:

63. Young Plasma Increases Median Lifespan Beginning at age 25.6 months , one rat group given young plasma every other week until death. Beginning human equivalent of 60-65 years “ Young Plasma Rejuvenates Blood DNA Methylation Profile, extends Mean Lifespan and Improves Physical Appearance in Old Rats” The Journal of Gerontology A; March 2, 2024: https://pubmed.ncbi.nlm.nih.gov/38430547/ https://pubmed.ncbi.nlm.nih.gov/38430547/ March 2, 2024 Survival curve of no treatment group began to decline at 26 months . From age 26 to 30 months , none of the young plasma animals died. The same age control group received no treatment. https://pubmed.ncbi.nlm.nih.gov/38430547/

64. Insert graph and 3-4 mouse photos from email I sent you on March 16 th at 1:43 AM Significant 9.1% improvement in median lifespan of the young plasma treated group (red) compared with no treated controls (black).

65. DNA methylation testing measures epigenetic age and is considered the most accurate method of assessing future morbidity/mortality risk. Young Plasma Reverses Epigenetic Age Improved insulin sensitivity, better immune & metabolic health, reduced inflammation! Epigenetic age stayed consistently lower in young plasma group until natural death with indications of: DNA methylation age of young plasma -treated rats beneficially fell below the control group

66. The longest-lived animal in control (no treatment) group. That’s where gene therapy can come to the rescue! Indicates young plasma can delay median death age but may not confer super longevity One interesting caveat… Indicates young plasma can delay median death age but may not confer super longevity That’s where gene therapy can come to the rescue! \

67. Reprogram old cells into induced pluripotent stem cells or young adult cells that can theoretically regenerate tissues forever . Yamanaka Transcription Factors –

68. There are about 1500 gene regulatory transcription factors Transcription factors can reprogram old cells into stem cells or young cells that regenerate tissues . Transcription factors   are proteins that help turn specific genes " on " or " off " by binding to DNA.

69. Octamer-binding factor 4 Original 4 Yamanaka Factors that Reversed Cell Aging Back in 2006 Yamanaka Transcription Factors OCT4 KLF4 SOX2 cMYC Acronym “ OSKM ”: c- Myelocytoatosis SRY-box factor 2 Kruppel -like factor 4

70. Octamer-binding factor 4 Original 4 Yamanaka Factors that Reversed Cell Aging Back in 2006 Yamanaka Transcription Factors OCT4 KLF4 SOX2 cMYC Acronym “ OSKM ”: c- Myelocytoatosis SRY-box factor 2 Kruppel -like factor 4

71. Octamer-binding factor 4 Just 3 Yamanaka Factors Reverse Aging in L ive Mice in 2022-2024 Yamanaka Transcription Factors OCT4 KLF4 SOX2 cMYC Acronym “ OSK ”: c- Myelocytoatosis SRY-box factor 2 Kruppel -like factor 4

72. Yamanaka OSK and other transcription factors Oct4 Sox2 KLF4 Oct4 Sox2 KLF4 OSK M Yamanaka Factors Deliver to Old Cells Oct4 Sox2 KLF4 Scientists have successfully reprogrammed old cells to stem cells, and then differentiated these stem cells back to their tissues of origin. These reprogrammed cells have the characteristics of young cells, which suggests that the characteristics of aging can be reversed. “Partial reprogramming” would be ideal for combating aging, in which old cells are converted directly to young cells without a stem cell intermediate. KLF4 Sox2 Intermittent OSK Expression Intermittent OSK Expression Partial Cell Reprogramming = Biological Age Reversal https://sitn.hms.harvard.edu/flash/2016/resetting-aging-clock-science-age-reversal/ Induced Pluripotent Stem Cell Maintain Youthful Cells: Newer Alternate Route Partial Reprogramming OSK Yamanaka Factors cMyc cMyc

73. But W hat Happens When Yamanaka Factors Are Delivered To Old Mice ? ? OSKM

74. March 9, 2022 “New research by the Salk Institute has shown cellular rejuvenation therapy safely reverses signs of aging in mice.” https://www.drugtargetreview.com/news/101826/scientists-have-shown-ageing-process-can-be-safely-and-effectively-reversed-in-mice/ “Scientists have shown aging process can be safely and effectively reversed in mice”

75. https://www.dailymail.co.uk/sciencetech/article-10589031/Scientists-REVERSE-ageing-mice-using-cellular-rejuvenation-technique.html Experts injected mice with molecules called the Yamanaka transcription factors  Treatment period of seven to 10 months was effective for restoring youthfulness The 'safe' treatment could one day help humans wind back their biological clock

76. Partial cell reprogramming in live (in vivo) mice OSKM (“Yamanaka”) transcription factors used No toxicity or increase in cancer detected Partial Cell Reprogramming – Safe https://www.nature.com/articles/s43587-022-00183-2 https://www.salk.edu/news-release/cellular-rejuvenation-therapy-safely-reverses-signs-of-aging-in-mice/ The Salk Institute Reports: “Cellular rejuvenation t herapy safely r everses signs of aging in mice” March 7, 2022

77. Cell reprogramming results in “ younger ” skin. Lower inflammation . Systemic Rejuvenation in Live Mice https://www.nature.com/articles/s43587-022-00183-2 https:// www.salk.edu/ news-release /cellular-rejuvenation-therapy-safely-reverses-signs-of-aging-in-mice/ Findings Reported in Nature: “Cellular rejuvenation therapy safely reverses signs of aging in mice” March 7, 2022 Reduced senescent - associated secretory phenotypes .

78. February 15 th , 2024 https://www.liebertpub.com/doi/10.1089/cell.2023.0072 “Gene Therapy-mediated Partial R eprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice “Together, these results may have important implications for the development of partial reprogramming interventions to reverse age-associated diseases in the elderly.”

79. https://pubmed.ncbi.nlm.nih.gov/?term=senolytic https://pubmed.ncbi.nlm.nih.gov/38381405/ Search of the National Library of Medicine Website February 26 th , 2024 Cyclic induction of OSK expression in 2-year-old wild type mice led to: >100% increase median remaining lifespan Improved health relative to control mice Profound age reversal in heart and liver tissues assessed by DNA methylation clocks Epigenetic age reversal in human cells that make up 90% of outmost skin layers

80. Improved Frailty Index Scores Aging increases susceptibility to adverse health outcomes that can be measured using a frailty index . This suggests that increased lifespan in response to OSK induction therapy correlated with overall better health . OSK treated mice had significant reduction in frailty index from 7.5 points in control mice to 6.0 points for OSK-treated  mice. High frailty compound scores reflect increase susceptibility to poor health outcomes.

81. Epigenetic Age R eversal of Human Skin Cells Exogenous induced overexpression of OSK in these keratinocytes led to significant epigenetic age reversal . K eratinocytes make up 90% of outer most skin layers. Keratinocytes isolated from scalp of 65-year-old male patient to assess effects of OSK .

82. AAV9 vector ( adeno-associated virus 9 )-( mouse proven ) Plasmid-based vector ( turn cells into bioreactors) Lipid nano-particles ( Intramuscular or intravenous ) Chemical reprogramming ( intravenous ) + Other viral vectors / intracellular delivery methods In vivo delivery methods being studied: For transcription factors to control longevity genes they must get inside of cells. Transporting Yamanaka Factors Inside Cells Transcription factors are DNA-binding proteins that control gene expression .

83. Two-part AAV system employed for systemic intracellular OSK delivery. Remarkable > 100% Extension in Median Remaining Life in Response to OSK Expression Control mice had 8.86 weeks of life remaining vs. 18.5 weeks in O SK-treated group Partial OSK reprogramming increased lifespan and improved frailty scores in old mice. Old mice equivalent to 77-year-old people used to enhance human translatability.

84. Remarkably, using 1/10th of the AAV at 1.7e11 vg/mouse, we observed robust OSK expression in the liver, heart, and spleen of both 8-week-old and 82-week-old mice ( Fig. 3 ). This encourages further investigation into the noninducible single OSK AAV's capacity to rejuvenate tissues and its impact on lifespan in future studies. The necessity for cotransduction of both AAVs (EF1a- rtTA4  and TRE- OSK ) into the same cell could potentially limit tissue distribution, hindering the observation of more extensive whole-body rejuvenation and a greater extension of lifespan. Considering the safety of continued OSK expression through AAV in the eye or liver for up to 21 months ( Karg et al.,  2023 ; Lu et al.,  2020 ), coupled with sustained vision improvement surpassing that of a cyclic OSK regimen ( Karg et al.,  2023 ), we engineered a single noninducible AAV vector ( pAAV -CMV- OSK ) to explore its potential to reach tissues in aged mice with reduced AAV titers. Minimal OSK Induction = Robust Age Reversal The 109% extension of remaining lifespan + improved frailty index + epigenetic DNA modifications occurred… with a fraction of the OSK dose delivered to cells. “This encourages further investigation into the noninducible single OSK AAV's capacity to rejuvenate tissues and its impact on lifespan in future studies.” “Remarkably, using 1/10th of the AAV at 1.7e11 vg/mouse, we observed robust OSK expression in the liver, heart, and spleen of both 8-week-old and 82-week-old mice”

85. Control mice having a remaining lifespan of approximately 5.09 human years. OSK-treated old mice with 18.5 weeks of life remaining would equate to 10.64 remaining human years in mouse-to-human aging approximation: C ontrol mice. February 26 th , 2024 https://pubmed.ncbi.nlm.nih.gov/38381405/ What Does This Equate to in Human Years? OSK -treated mice lived longer in better health . OSK -treated mice having a remaining lifespan equating to approximately 10.64 human years.

86. What Happened in early 2024 OSK transcription factors reversed epigenetic age, improved overall health and extended remaining lifespans >100% in old rats…research advancing to old monkeys . Exosome-rich young plasma cut old rat epigenetic ages in half and improved overall health…research now advancing to dogs . Next steps: Replicate these findings in murine models while simultaneously initiating OSK and young plasma research in old primates . Young plasma reversed epigenetic aging in old rats and increased median lifespan human equivalent of about 7 years . 1) 2) 3 )

87. https://link.springer.com/article/10.1007/s11357-024-01269-y July 22, 2024 Geroscience This study partially funded by the Life Extension® group Our study was supported in part by research grant (Grant # SEGR-9–23-21) from  the Society for Experimental Gerontological Research (SEGR)   and grant PICT 2018–00907 to RGG. Part of the funding was provided by Open Philanthropy (Horvath). Funding:  July 22, 2024

88. https://link.springer.com/article/10.1007/s11357-024-01269-y July 22, 2024 Significantly improved learning performance. Trends toward epigenetic age reversal in hippocampus region of the brain. Geroscience Yamanaka factors ( OSKM ) injected into hippocampus brain region (where memories are stored): Improved spatial memory to lesser extent. Rejuvenation of hippocampal epigenome .

89. Form new memories Learning Emotions https://www.verywellmind.com/what-is-the-hippocampus-2795231 Hippocampal Region of Brain Three primary functions of hippocampus brain region:

90. “Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy” "Latency time" refers to time taken for rat to locate escape platform. Old- OSKM-treated rats show beneficial ( 36% reduction ) in latency time compared to old controls . Old Control Old OSKM- Treated \ Effect on Learning

91. “Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy” Old-OSKM-treated rats show improved learning performance compared to old controls, but latency time to escape not fully restored to youth. \ Effect on Learning Mouse navigating Barnes maze test:

92. “Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy” OSKM -treated mice show a 30% improvement of memory performance compared to old controls, but memory not fully restored to young mice. Old Control Old OSKM- Treated \ Effect on Memory OLD CONTROL YOUNG OLD OSKM

93. 2006 : cell reprogramming demonstrates cell rejuvenation . 2011 : Rejuvenation induced in very old human cells ( in vitro ) 2022 : Aging partially reversed in live mice (independent studies) 2024-2027 : Research to rejuvenate old monkeys & humans . Prior biology doctrine: Cell rejuvenation not possible. Rapid Transition of Age Reversal from Cells to Mice to Monkeys to Humans --> Rewriting the Rules of Biology | https://pubmed.ncbi.nlm.nih.gov/33627519

94. Discover the latest breakthroughs in research Learn how to critically evaluate longevity data See what lifestyle interventions can positively impact longevity and quality of life Oct 26, 2023 World’s Largest Bank Focuses on H ealthy Longevity World’s Largest Bank Focuses on Healthy Longevity World’s Largest Bank Focuses on Longevity Learn how to critically evaluate longevity data See what lifestyle interventions can positively impact longevity and quality of life Discover the latest breakthroughs in research

95. Discover the latest breakthroughs in research Learn how to critically evaluate longevity data See what lifestyle interventions can positively impact longevity and quality of life Oct 26, 2023 World’s Largest Bank Focuses on H ealthy Longevity World’s Largest Bank Focuses on Healthy Longevity World’s Largest Bank Focuses on Longevity Learn how to critically evaluate longevity data See what lifestyle interventions can positively impact longevity and quality of life Discover the latest breakthroughs in research

96. Highlights from the JP Morgan Longevity Webcast Think of your body as a " depreciating asset .” 93% of your lifespan determined by lifestyle choices; only approximately 7% affected by genetics . Think of longevity in investing terms, such as food choices and sleep being " accounts " that you can " invest in " for better health and longevity. U.S. medical system should change to reprioritize preventative medicine . If you do most of the best lifestyle choices, you can expect to live 15-25 years longer. Aggressive screening/testing to catch diseases early . Oct 26, 2023

97. Level 1 essential to sustain life Optimal Health Level 2 Level 1 - Hormones                     - Renal function - Apolipoprotein B       - Sleep quality - Blood Pressure              - Glucose - C-reactive protein        - Homocysteine - Insulin                            - Coagulation Death Level 1 …Essential to sustain life Harsh Reality! Failure To Correct Proven Risk Factors

98. Level 1 is essential to progress to Level 2 Optimal Health Level 2 Level 1 - Hormones                     - Renal function - LDL/ApoB                  - Sleep quality - Blood Pressure              - Glucose - C-reactive protein        - Homocysteine - Insulin                            - Coagulation Underlying Risk Factors Individualized Age Reversal Interventions House of Optimal Health Correct Your

99. House of Optimal Health - Hormones                     - Kidney function - LDL/ApoB                  - Sleep quality - Blood Pressure              - Glucose - C-reactive protein         - Homocysteine - Insulin                             - Coagulation - Senolytics - NAD + Restoration - mTOR-inhibition - Exosomes - Mesenchymal Stem Cells - Mitochondria Transfer - Young Plasma/Blood filtering Failure to optimize Level 1 , preclude benefits of Level 2 . Optional Approaches Healthy Aging - Perinatal tissues - Hyperbaric - Gene therapy Level 2 Level 1

100. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940111 “We’ve shown, for the first time, how steadily accumulating mutations throughout life lead to a catastrophic and inevitable change in blood cell populations after the age of 70.” Levine-Horvath Phenotypic Age Model ‘Phenotypic Age’ estimate based on clinical measures of 9,926 adults with complete biomarker (blood test) data Analyzed data from over 23 years of mortality follow-up Advanced computational/statistical methods identified 9 phenotypic blood test markers that predict morbidity / mortality risk

101. Bill’s calculated phenotypic (biological) age 11.12 younger than chron age and difference Albumin Creatinine Glucose CRP (C-reactive protein) Lymphocytes MCV (m ean corpuscular volume) RDW ( red cell distribution width) Alkaline phosphatase White Blood Cells WBC 3.8 11.12 -year younger phenotypic age compared to chronological age “An epigenetic biomarker of aging for lifespan and healthspan ”- www.ncbi.nlm.nih.gov/pmc/articles/PMC5940111 Standard Blood Chemistry + CRP enables Phenotypic (Levine-Horvath) measure of B iological A ge :

102. “Accelerated aging linked to cancer risk in younger adults…” April 7 th , 2024 www.cnn.com/2024/04/07/health/accelerated-aging-cancer-risk Phenotypic age used to calculate biological age of 148,000 people in UK. Compared to those with the youngest biological age those aging the fastest had: 80% increased risk for uterine cancer 60% higher gastrointestinal tumors Twice the risk of early onset lung cancer Phenotypic age is calculated from standard CBC/Chem + C-reactive protein blood tests.

103. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2819335 May 13, 2024 “Healthy Lifestyle and the Likelihood of Becoming a Centenarian” JAMA Network Open.  2024;7(6):e2417931. doi:10.1001/jamanetworkopen.2024.17931 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2820220   23% death reduction with highest adherence to Mediterranean diet: Blood Tests Predict Human Longevity Lower homocysteine , triglycerides (other lipids) Lower C-reactive protein (other inflammatory markers) Lower creatinine (kidney) Lower insulin resistance (diabetic markers) Lower body mass Higher alanine & citrate (mitochondria & protein synthesis) Reduced death risks were associated with:

104. Commercial Lab : $720 Age Reversal Project : $85 + Phenotypic Age score at no cost Phenotypic Blood Tests to Calculate Biological Age: + A1C + Lipids + Fasting Insulin Complete Blood Count-Chemistry + C-reactive protein

105. Cardiac/Inflammatory Markers NMR Lipoprofile (atherogenic lipid risks + inflammation markers) Homocysteine C-Reactive Protein (high sensitivity) Apolipoprotein B ) Magnesium (serum) Hormones and Binding Proteins IGF-1 IGF1BP3 DHEA-S Free Testosterone Total Testosterone Estradiol Progesterone Vitamin D 25-Hydroxy Thyroid Function Free T3 Free T4 TSH (Thyroid Stimulating Hormone) Insulin Resistance Markers Insulin HbA1C Ferritin Glucose, Liver-Kidney Function Glucose Uric Acid BUN Creatinine eGFR BUN/Creatinine Sodium Potassium Chloride Calcium Phosphorus Protein, Total Albumin Globulin Bilirubin Alkaline Phosphatase LDH AST ALT GGT Iron Conventional Markers , Cholesterol, Total Triglycerides HDL Cholesterol LDL Cholesterol T. Chol/HDL Ratio Estimated CHD Risk Men * PSA (prostate cancer) Age Management Panel retails for around $4,000 at commercial labs. $396 at RAADfest or Age Reversal Network https://www.lifeextension.com/lpages/2019/ine801e

106. DNA Methylation (epigenetic age) Blood Tests at RAADfest https://www.trudiagnostic.com/ https://clockfoundation.org/ https://dexabody.com/ Bone Density/Body Composition at RAADfest + or

107. How to Accelerate Degenerative Illnesses Dangerous Lifestyles Preclude Healthy Aging P Deadly Foods Tobacco Use Low intake of Fruit/Vegetables Neglect Preventive Healthcare Dangerous Patterns Premature Aging Unhealthy Lifestyles

108. Change year 2020 to 2024

109. We Don’t Have Time for Delayed Age Reversal Human Research

110. 1906-2024 = 118 Years of Needless Delays

111. Human Age Reversal Project $1,215,000 Goal: Statistically Significant Human Age Reversal age-reversal. n e t /donate

112. Life Extension® published-advocated for FDA approval or thymosin alpha -1 in its newsletter (Anti-Aging News) in 1981 . Front page of November 1981 issue of Anti-Aging News Life Extension® Published / advocated for FDA approval of thymosin alpha -1 in 1981 . Life Extension® published and advocated for FDA approval of thymosin alpha-1 in 1981 .

113. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742685/ 2019 2019; 9. 873.

114. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747025/ Thymosin alpha 1: A comprehensive review of the literature World J Virol .   2020 Dec 15; 9(5): 67–78. Thymosin alpha 1 is a peptide naturally occurring in the thymus that has long been recognized for modifying, enhancing, and restoring immune function. Thymosin alpha 1 has been utilized in the treatment of immunocompromised states and malignancies, as an enhancer of vaccine response, and as a means of curbing morbidity and mortality in sepsis and numerous infections. Studies have postulated that thymosin alpha 1 could help improve the outcome in severely ill corona virus disease 2019 patients by repairing damage caused by overactivation of lymphocytic immunity and how thymosin alpha 1 could prevent the excessive activation of T cells. In this review, we discuss key literature on the background knowledge and current clinical uses of thymosin alpha 1. Considering the known biochemical properties including antibacterial and antiviral properties, time-honored applications, and the new promising findings regarding the use of thymosin, we believe that thymosin alpha 1 deserves further investigation into its antiviral properties and possible repurposing as a treatment against severe acute respiratory syndrome coronavirus-2. 2020

115. https://pubmed.ncbi.nlm.nih.gov/35364609/ 2022

116. https://pubmed.ncbi.nlm.nih.gov/36812669/ 2023

117. https://pubmed.ncbi.nlm.nih.gov/38308608/ Objective:  This study aims to assess the safety and efficacy of Thymosin Alpha 1 (Tα1) through a comprehensive narrative review of clinical studies involving over 11 000 human subjects in more than 30 trials. The focus was on Tα1's application in COVID-19, autoimmune conditions, and cancer treatment, with implications for future considerations. Methods:  We systematically searched articles relevant to critical studies on COVID-19, infectious diseases, cancer, and autoimmune diseases indexed on Pubmed , Google Scholar, and Cochrane Library. Our focus was on evaluating the safety and efficacy of Tα1 in human subjects. Clinical trials conducted worldwide involving diverse populations were analyzed to assess the safety and effectiveness of Tα1. The review examines explicit outcomes in over 11 000 human subjects, emphasizing its role in addressing COVID-19, autoimmune conditions, and cancer treatment. Results:  Contrary to the FDA's restriction on Tα1 and 21 additional peptides in 2023, our analysis reveals consistent evidence of Tα1's safety and efficacy. The peptide has demonstrated significant effectiveness in treating various conditions, including COVID-19, autoimmune disorders, and cancer. This review summarizes conclusions drawn from a comprehensive examination of clinical trials worldwide. Conclusions:  Based on substantial evidence from clinical trials, Tα1 emerges as a well-tolerated and effective immune modulator. The FDA›s restriction appears unfounded, as Tα1 has shown safety and efficacy beyond the initially specified conditions. Urgent attention and intervention are warranted to ensure the continued availability of this life-saving peptide through prescription. Therefore, it is recommended that the FDA permits 503A compounding pharmacies to compound Tα1, considering its potential to treat a variety of conditions effectively. Comprehensive Review of the Safety and Efficacy of Thymosin Alpha 1 in Human Clinical Trials Alternative Therapies 2024 “The FDA’s restriction appears unfounded, as thymosin a1 has shown safety and efficacy beyond the initially specified conditions.”

118. https://pubmed.ncbi.nlm.nih.gov/30063866/   Published online : 31 Jul 2018 2018

119. Back page of November 1981 issue of Anti-Aging News After 42 years , most doctors are unaware that thymosin alpha-1 has anti-aging , anti-viral and anti-cancer effects.

120. Bridging the Longevity Gap Urgent Need to Reform Clinical Trial Regulations Scientific Advances Consumer Access FDA

121. https://en.wikipedia.org/wiki/Flying_Machines_Which_Do_Not_Fly https://bigthink.com/pessimists-archive/air-space-flight-impossible/ In 1903, New York Times predicted that airplanes would take 10 million years to develop Only nine weeks later, the Wright Brothers achieved manned flight. The pathologically cynical always will find a reason to complain. 9 weeks later…Wright Brothers achieve manned flight. - October 7th, 1903 In October 1903, The New York Times Proclaimed It Would Take 10 Million Years to Develop Airplanes

122. December 17, 1903 First flight: 120 feet/20 feet off ground

123. July 1969 December 1903 66 Years from Kitty Hawk to Man on Moon

124. Age Reversal Compared to Jet Air Travel 1903 1957 Heavier-than-air flight Commercial Jet Travel 2006 2019-2024 Age Reversal in Cells Human & Live Animal Age Reversal Rapid Biomedical Advances!

125. Founded most successful quantitative hedge fund of all time. His Medallion Fund earned more than $100 billion in trading profits between 1988-2018. Donated $billions to scientific research. Dead at age 86. Who missed the longevity boat? Jim Simmons ( 1938 – 2024) Expiration date: May 10, 2024 Net Worth > $31 billion https://www.cnbc.com/2024/05/10/jim-simons-billionaire-quantitative-investing-pioneer-who-generated-eye-popping-returns-dies-at-86.html Quantitative Investing Pioneer

126. The Prospect of Human AGE REVERSAL Aging has been delayed & reversed in animal models. Human studies show partial age-reversal . Interventions to combat degenerative aging being utilized today!

127. age-reversal.net View this entire presentation at:

128. Any Questions

129. Unparalleled Track Record of Biomedical Innovation First Established 1977

130. Age Reversal Advances from Cells to Mice, Monkeys and Humans  RAADfest 2024 – Anaheim, CA Sept 5 th , 2024 Bill Faloon Life Extension®