Bill Faloon on what's delaying regenerative medicine in 2023.pptx

1. Marriott Hotel West Palm Beach, Florida William Faloon February 9th 2023 What’s Delaying Regenerative Medicine?

2. Unparalleled Track Record of Biomedical Innovation First Established 1977

3. World’s Largest Longevity Organization https://www.lifeextension.com/about/life-extension-story/history

4. age-reversal.net This presentation and info about aging research available at:

5. “FDA is responsible for advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable…”1 1. https://www.fda.gov/about-fda/what-we-do FDA Headquarters, Rockville, Maryland

6. What FDA says: “FDA is responsible for advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable…”1 “FDA is responsible for impairing the public health by delaying innovations that make medical products less effective, less safe, and less affordable…”2 What FDA does: = Needless Deaths 2. FDA Holocaust Museum- 1994-2022

7. "We stand on the cusp of a revolution in health care. Advances in molecular medicine will allow us to develop powerful new treatments that can cure or even prevent diseases like Alzheimer's and cancer."1 "What's missing," according to Dr. von Eschenbach: 1.https://www.lifeextension.com/magazine/2012/12/former-fda-commissioner-admits-risk Former FDA commissioner Andrew von Eschenbach, M.D.:

8. FDA Commissioner Margaret Hamburg’s sworn testimony: 1.https://www.lifeextension.com/magazine/2012/12/former-fda-commissioner-admits-risk Margaret Hamburg M.D.

9. https://www.cato.org/commentary/rethinking-fda “If the FDA delays a good drug, the cost is less obvious because most of those affected are not aware their illness could have been treated more effectively. A great deal of evidence supports this perspective and estimates huge life‐saving benefits would be derived from greater speed.” August 24th, 2022 “Scientists have shown aging process can be safely and effectively “Rethinking the FDA”

10. January 6, 2023 “The reversal of aging could hinge on one huge decision.” “If the FDA classifies aging as a disease, drug companies can take a new approach to curing death.” https://www.popularmechanics.com/science/health/a42419017/anti-aging-drugs-fda-approval/ “Humans Can Start Living Longer —Once the FDA Does This” “Scientists are already targeting proteins in cells to keep them from degenerating.” “TheWHOsupportsthegrowingtrendofcallingagingadisease.”

11. | Jan. 11, 2023 “FDA Increasingly Halting Human Trials…” Clinical holds by FDA can stifle progress: 2017-2020: 557 clinical holds* 2002-2021: 664 clinical holds 2021-2022: 747 clinical holds “FDA is also saying that's probably part of the reason it's having to press pause on more trials because the technology is just so new.” *average each year

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

13. Feb 23 /March 2, 2015 TIME describes the prospect of delayed aging. Early Media Report Year 2015

14. May 2017

15. https://www.pressreader.com/usa/popular-science/20180505/281672550562011 “Bill Faloon has pursued immortality for decades. Now he’s got lots of company. What does science have to say?” “The FOREVER Man” May 5, 2018

16. https://www.newscientist.com/article/mg23931920-600-how-a-positive-mind-really-can-create-a-healthier-body/ “He stirred controversy with his plans to bring back the woolly mammoth. But first he’s working on editing sperm – and trying out his aging reversal techniques on dogs.” “George Church: The maverick geneticist now wants to reverse aging” August 25th, 2018

17. April 27, 2019 https://www.newscientist.com/issue/3227/

18. According to Juvenescence’s Greg Bailey “We won’t be aging as fast or poorly as our parents” “I think the world is going to be shocked” Juvenescence has now raised $165 million to fund longevity projects with the goal of extending human lifespans to 150 years. “Science fiction has become science” ‘Extraordinary’ Breakthroughs In Anti-Aging Research ‘Will Happen Faster Than People Think’ https://www.forbes.com/sites/robinseatonjefferson/2019/08/26/how-extraordinary-breakthroughs-in-anti-aging-research-will-happen-faster-than-people-think

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

20. “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 used individualized doses of: Study subjects also provided with daily vitamin D3 and zinc.

21. 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.”

22. - July 19, 2022

23.  Once-faltering paws gripped objects with renewed strength.  Hearts and livers of rats regained youthful vitality.  Fuzzy memories sharpened.  Biological age had been cut in half. “It was as if someone had turned back time.” April 30, 2022 “GrowingYounger:RadicalInsights IntoAgingCouldHelpUsReverse It” April 30,2022|https://www.newscientist.com/issue/3384/

24. June 7 2022 https://www.technologyreview.com/2022/06/07/1053132/saudi-arabia-slow-aging-metformin/ The oil kingdom fears that its population is aging at an accelerated rate and hopes to test drugs to reverse the problem. First up might be the diabetes drug metformin. Saudi Arabia Plans To Spend $1 Billion A Year Discovering Treatments To Slow Aging of its oil wealth supportingbasic research on the biology of aging and findingwaysto extend the number of years people live in good health $1 BILLION A YEAR has started a not-for-profit organization called the Hevolution Foundation that plans to spend up to “ ”

25.  The field of geroscience aims to find ways to delay onset of age-related diseases.  Geroscience experts met virtually at a symposium of the New York Academy of Sciences.  Advances made in understanding the mechanisms underlying biological aging. “The presentations focused on identifying biomarkers of aging and the search for interventions to prevent and treat age-related diseases.” https://www.medscape.com/viewarticle/985809 “FDA does not recognize aging as an indication for drug approval…” December19th,2022

26. https://www.nationalgeographic.com/magazine/article/aging-cure-longevity-science-technology-feature/ Dec. 28, 2022

27. “A Drug to Treat Aging May Not Be a Pipe Dream” “By the end of 2023, it’s likely that one of these ideas will be shown to work in humans.” www.wired.com/story/drugs-aging-medicine-biotech/ ►“In 2023, early success of these treatments could kickstart the greatest revolution in medicine since the discovery of antibiotics.” ►“Senolytics aren’t the only contenders…but the success of a drug targeting an aspect of aging in clinical trials will allow us to consider this loftier goal in the not-too-distant future.” Jan. 1st, 2023 New approaches to the biology of senescence can make lives longer and healthier.

28. The start-ups seeking a cure for old age  Eric Verdin, chief executive of the Buck Institute, “scientists have completely changed how they think about ageing” “Tech billionaires are funding research to help us live longer and healthier lives” “Thestart-ups seeking acureforoldage” January 2, 2023 https://www.ft.com/content/649b0446-698c-4363-82ad-0be5b5faa68f  Nir Barzilai, Institute for Aging Research at Albert Einstein College of Medicine “the world is on the cusp…of finding transformational drugs that prevent the effects of ageing…”  Mehmood Khan, chief executive of Hevolution Foundation (Saudi Arabia), “its vision is to “extend healthy lifespan for the benefit of all humanity”

29. March 7, 2022 Scientists Reverse Aging in Mice

30. March 11, 2022 “Anti-Aging Breakthrough: https://scitechdaily.com/anti-aging-breakthrough-cellular-rejuvenation-therapy-safely-reverses-the-aging-process-in-mice/ Cellular rejuvenation therapy safely reverses signs of aging in mice. Credit: Salk Institute Cellular Rejuvenation Therapy Safely Reverses the Aging Process in Mice”

31. March 9, 2022 “Newresearchbythe SalkInstitutehasshown cellularrejuvenation therapysafelyreverses signsofaginginmice.” 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”

32. 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

33. March 7, 2022 https://www.salk.edu/news-release/cellular-rejuvenation-therapy-safely-reverses-signs-of-aging-in-mice/ Mar. 7, 2022 “Scientistssafelyandeffectivelyreversetheagingprocessinmiddle-aged andelderlymicebypartiallyresettingtheircellstomoreyouthfulstates.”

34. • Partial cell reprogramming in live (in vivo) mice • OSKM (“Yamanaka”) transcription factors used • Longeradministrationdemonstrateduniquebenefits • 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/

35. Transcription factors can enable old cells to be reprogrammed into embryonic cells capable of developing into all tissues of the body. Transcription factors are proteins that help turn specific genes "on" or "off" by binding to DNA. Groups of transcription factors can turn a gene on/off in specific parts of the body. Transcription factors that are repressors decrease transcription. Transcription factors that are activators boost a gene’s transcription.

36. The Nobel Prize in Physiology or Medicine 2012 These transcription factors are called: “Yamanaka Factors” Four specific genes encode transcription factors that can convert somatic cells into pluripotent stem cells that can propagate indefinitely. nobelprize.org/prizes/medicine/2012/yamanaka

37. https://hms.harvard.edu/news/loss-epigenetic-information-can-drive-aging-restoration-can-reverse “Study in mice implicates changes to way DNA is organized, regulated rather than changes to genetic code itself” “Loss of Epigenetic Information Can Drive Aging, Restoration Can Reverse It” Jan.12th,2023 1 “the extensive experiments led the team to conclude that “by manipulating the epigenome, aging can be driven forwards and backwards”

38. Jan 12, 2023 https://www.cnn.com/2023/01/12/health/reversing-aging-scn-wellness/index.html “Old Mice Grow Young Again… Can People Do The Same?”  Harvard researchers show aging may be caused by changes in epigenetic markers.  Damaged DNA caused marked acceleration in epigenetic age of mice.  Researchers may have induced aging by damaging DNA in mice.

39. “Scientists Have Reached a Key Milestone in Learning How to Reverse Aging” Jan. 12th, 2023  Researchers then used pluripotency factors “OSK” to reversesomeofthisapparentaging.  Age-related dysfunction might be reversible by modifying epigenetic status.  Results suggest that aging might be controlled by epigenetics. https://time.com/6246864/reverse-aging-scientists-discover-milestone/

40. • Long-termcell reprogrammingresults in “younger”skin age. • Skin cells divide more rapidly. • Lower inflammation and reduced senescent-associated secretory phenotypes in treated animals. • No data collected on lifespan, exercise, memory, or muscle. Cell 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/

41. - January 9th, 2023 technologyreview.com/2023/01/09/1066488/biotech-says-mice-live-longer-after-genetic-reprogramming/ This Biotech Startup Says Mice Live Longer After Genetic Reprogramming “A small biotech company claims it has used a technology called reprogramming to rejuvenate old mice and extend their lives, a result suggesting that one day older people could have their biological clocks turned backwithaninjection—literally becomingyounger.”

42. Scientists at Rejuvenate Bio recently tested epigenetic reprogramming in elderly mice Jan. 5th, 2023 They gave 124-week-old mice gene therapy with three Yamanaka factors: OSK They reported that remaining lifespan was more than doubled with treatment Reference: https://www.biorxiv.org/content/10.1101/2023.01.04.522507v1 *Study has not yet been peer reviewed as of 1/24/2023. Frailty was also reduced in treated mice

43. Jan. 5th, 2023 Yamanaka factors production capacity induced in vivo in normal aged mice. Expression of Yamanaka factors controlled by oral doxycycline administration. Human equivalent doubling of remaining lifespan started in late life might enable: Reference: https://www.biorxiv.org/content/10.1101/2023.01.04.522507v1 A 70-year-old with a life expectancy of 15 years to have it extended to 31 years.

44. Jan.5th,2023 Old mice injected with the Yamanaka factor encoded virus. Adeno-associated virus encoded with three Yamanaka factors (OSK) (Doxycycline used as Yamanaka factor promoter.) Doxycycline in drinking water (one week on and one week off) controllably promotes Yamanaka factors. The start-ups seeking a cure for old age RESULTS ► Reversal of epigenetic aging markers ► Restored youthful functions ► Extension of remaining lifespan by 109% Reference: https://www.biorxiv.org/content/10.1101/2023.01.04.522507v1 *Study has not yet been peer reviewed as of 1/24/2023.

45. After large animal research, next step may be testing old people. ►Researchers can order Yamanaka factor-encoded viral vectors from certified biologics suppliers. What may be studied next…. ►Inject into old dogs and old primates. ►Test differing doxycycline dosing schedules to turn on Yamanaka factors and measure effects on aging. Jan. 5th, 2023

46. > 2006: cell reprogramming demonstrates cellular rejuvenation. > 2011: Rejuvenation induced in very old human cells (in vitro) > 2022: 100% of Human Genome sequenced. > 2022: Aging partially reversed in live mice (SALK) > 2022: Research underway to rejuvenate old humans. https://pubmed.ncbi.nlm.nih.gov/33627519 Cellular Reprogramming --> Rewriting the Rules of Biology | https://pubmed.ncbi.nlm.nih.gov/33627519 > 2023: Aging partially reversed in live mice (Harvard + bioRxiv)

47. September 02, 2022 | https://doi.org/10.1111/acel.13696 September 2nd, 2022

48. “Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers” Human Study • Each injection equivalent to 100 mL umbilical cord plasma infusion. September 02, 2022 | https://doi.org/10.1111/acel.13696 • 18 human participants average age 74 years. • Safety-efficacy evaluated with blood tests + GrimAge® epigenetic clock. • Weekly injection of umbilical cord plasma concentrate into muscle for 10 weeks. (Fourumbilicalcordsusedtoproduceeachweeklyinjection.)

49. • GrimAge®: -0.78yearsyounger(predictorofdeathrisk) • 30% of 90 biomarkers changed beneficially, zero negatively • No significant side effects • Kidney function: 7% improvement measured by eGFR (+ 5) • Phenotypic Age Score biomarkers such as RDW and MCV improved, reducing predicted age September 2nd, 2022 https://onlinelibrary.wiley.com/doi/10.1111/acel.13696

50. Scientists have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research. “The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.” Jianfeng Lan, Jarod A. Rollins, Xiao Zang, Di Wu, Lina Zou, Zi Wang, Chang Ye, Zixing Wu, Pankaj Kapahi, Aric N. Rogers, Di Chen. Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity. Cell Reports, 2019; 28 (4): 1050 DOI: 10.1016/j.celrep.2019.06.078 “Pathways that extend lifespan By 500 percent identified” Jan 8, 2020

51. https://www.webmd.com/healthy-aging/story/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. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself.” Feb 20, 2021 Is There a Cure for Aging?

52. February 10, 2021

53. Dec. 30, 2020 https://fortune.com/2020/12/30/anti-aging-research-health-care-spending-biden/ Mainstream Recognition of The Need to Reverse Human Aging “Age is the biggest risk factor for cancer, cardiovasculardisease,andneurodegeneration. Withouttreatmentsto slowor reverseaspects of biologicalaging,anagingpopulationmeans we areinfor ahealthcarecosttsunami. With such treatments, Americans would experiencemorehealthy,productiveyearsoflife.”

54. “…why not launch an Operation Warp Speed for biological aging?” CONCLUSION https://fortune.com/2020/12/30/anti-aging-research-health-care-spending-biden/ December 30, 2020

55. Bridging the Longevity Gap Urgent Need to Reform Clinical Trial Regulations

56. o 1497: Citrus shown to cure scurvy o 1747: James Lind proves citrus cures scurvy o 1870: Flawed study discredits “citrus cure” o 1911: Dr. Robert Scott loses crew to scurvy o 1932: Vitamin C proven to cure scurvy Thousands of Deaths After Scurvy Cure Discovered

57. Delays Caused Needless Deaths From Bacterial Infections •Antibiotic properties of penicillin discovered:1928 •Alexander Fleming’s findings published: 1929 •Penicillin not widely available until 1946 Millions of preventable deaths! Alexander Fleming

58. Penicillin Availability 1928 1946 HumanAge Reversal ? 2015

59. Daily Deaths of Americans > age 64: https://www.cdc.gov/nchs/fastats/older-american-health.htm 6,800 Human Lives Lost

60. The subcutaneous administering of 9 million international units a day of the drug interleukin-2 to pancreatic cancer patients three days before surgery induced the following benefits compared to placebo patients administered saline: 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%

61. Survival of Prostate Cancer Patients with Poor Prognosis: Not Supplemented with melatonin: 5.34 Years Supplemented with 3 mg of melatonin: 12.8 Years Seven years increased survival in melatonin-treated patients after conventional treatment failure.

62. Dozens of companies selling Fisetin for years… But does it have “senolytic” properties in humans?

63.  Professor James Kirkland at Mayo Clinic spearheading studies of fisetin.  Dr. Kirkland describes clinical trial where FDA made him complete a 450 page- detailed Investigational New Drug application.  This had to be submitted to the FDA for approval to do a human study using fisetin.  FDAthen mandates Kirkland doanimal and pharmacology studies before “allowing” aclinical trial.  Fisetin has been ingested by people in various fruits and vegetables. It’s also been used for years as a dietary supplement. It took 2.5 years for human study begin. Example of FDA Delay of Clinical Trial on Fisetin Bureaucratic barriers impede rapid testing compounds that may slow/reverse aging processes. Available at: https://www.youtube.com/watch?v=yqjuWdWtJF8. Accessed August 9, 2022.

64. Store Shelves Today are Packed with Dietary Supplements

65.  FDA seeks to classify most dietary supplements as prescription drugs.  Pharma spends huge amounts lobbying Congress.  One Senator stands in FDA’s way.  Vitamin consumers inundate Congress with protests. Near certain victory for FDA fails as Congress votes down anti- supplement legislation. August 15, 1974

66.  In early 1970’s FDA tried to re-classify many food supplements into prescription drugs.  Pharma heavily lobbied to gain exclusive access to sell supplements.  The Proxmire Amendment made it so that food supplements could not be classified as drugs, making their sale possible without a prescription from a doctor.  The Proxmire Amendment and others he spearheaded became section 411 of the Federal Food, Drug, and Cosmetic Act. One Senator Saved Consumer Open Access to Dietary Supplements 1974-1976 Legislative Period Senator William Proxmire en.wikipedia.org/wiki/The_Proxmire_Amendment

67. GNC Indicted for Promotion of Primrose Oil Nov. 15th, 1984 https://www.nytimes.com/1984/11/15/us/health-food-company-is-indicted-on-promotion-of-oil-of-primrose.html Reason: FDA says no studies support safety/efficacy of primrose oil. Investigation: Criminal investigation initiated in 1980. FDA threat: GNC executives threatened with 5-year jail sentence. Outcome: GNC corporation & two executives plead guilty. GNC stops promoting primrose oil.

68. https://pubmed.ncbi.nlm.nih.gov/?term=oil%20of%20evening%20primrose Dec .31st , 2022 HundredsofPublished Scientific StudiesSupportBenefits ofPrimroseOil

69. • Atopic dermatitis • Inflammatory disorders • Peripheral neuropathy • Autoimmune conditions • Renal function • Rheumatoid arthritis • Post menopausal symptoms • Reduced cardiovascular risk factors Potential Benefits of Evening Primrose Oil References on following 36 slides of published scientific abstracts

70. Prostaglandins Leukot Med. 1982 Jun;8(6):641-5. Protection against ethanol-induced embryonic damage by administering gamma-linolenic and linoleic acids P K Varma, T V Persaud PMID: 6287501 Abstract Many reports have now confirmed the teratogenic potential of alcohol in humans and in laboratory animals. A characteristic pattern of congenital anomalies is present in infants born to mothers suffering from chronic alcoholism. The pathogenesis of this condition is unclear. Chronic consumption of ethanol causes a depletion of essential fatty acids, partly by blocking gamma-linolenic acid formation and partly by depleting dihomogammalinolenic acid. Whether this action of ethanol on essential fatty acid and prostaglandin metabolism may account for its teratogenic potential was investigated in the rat. Treatment of pregnant rats with ethanol and evening primrose oil (efamol), a rich source of gammalinolenic acid, led to a significant reduction in the embryopathic activity of ethanol. https://pubmed.ncbi.nlm.nih.gov/6287501/

71. Rheumatol Int. 1984;4(4):165-7. Primary Sjögren's syndrome treated with Efamol/Efavit. A double-blind cross-over investigation R Manthorpe, S Hagen Petersen, J U Prause PMID: 6385206 DOI: 10.1007/BF00541208 https://pubmed.ncbi.nlm.nih.gov/6385206/ Abstract Thirty-six patients with primary Sjögren's syndrome participated in a randomised double- blind, cross-over, 3-week, study to compare the effect of Efamol (1500 mg X 2) with that of placebo. Efamol contains 9% of the prostaglandin-E1 precursor gamma-linolenic acid, which is presumed to occur in reduced levels in Sjögren's syndrome. Efamol treatment improved the Schirmer-I-test (P less than 0.03) while values of break-up time,-van Bijsterveld score, corneasensitivity, tear-lysozyme and nuclear chromatin in conjunctival epithelial cells did not reach the statistical 0.05 level.

72. Atopic dermatitis and essential fatty acids: a biochemical basis for atopy? S Wright PMID: 3890448 DOI: 10.2340/00015555114143145 Abstract The effects of dietary supplementation with evening primrose oil (Efamol) in 99 patients with atopic dermatitis were investigated in a double blind, controlled crossover study. Simultaneously, plasma phospholipid essential fatty acid status was determined in 50 of these patients before and after treatment. In a separate study, lymphocyte subsets and mitogen responses were investigated in 15 atopic patients before and after treatment. The conclusion is that evening primrose oil improves atopic dermatitis; an abnormality of the enzyme delta-6- desaturase is proposed to explain the biochemical findings. Finally, it is concluded that the therapeutic effect of evening primrose oil is unlikely to be mediated through a primarily immunological mechanism. Atopic dermatitis and essential fatty acids: a biochemical basis for atopy? Clinical Trial Acta Derm Venereol Suppl (Stockh). 1985;114:143-5. https://pubmed.ncbi.nlm.nih.gov/3890448/

73. Beneficial effects of polyunsaturated fatty acids in partially nephrectomized rats Prostaglandins. 1986 Aug;32(2):211-9. U O Barcelli, J Miyata, Y Ito, L Gallon, P Laskarzewski, M Weiss, R Hitzemann, V E Pollak PMID: 3797690 DOI: 10.1016/0090-6980(86)90126-7 Abstract Evening primrose oil, safflower oil, and salmon oil, all with high polyunsaturated fatty acid content, were fed to partially nephrectomized rats; the effects were compared to those of feeding beef tallow. All three oils had favorable effects on progression of renal failure, salmon oil on kidney histology as well. The changes induced in platelet production of thromboxane A2, and in the renal production of various eicosanoids may explain the protective role of these oils. https://pubmed.ncbi.nlm.nih.gov/3797690/

74. A Dib 1 , J P Carreau PMID: 2821872 DOI: 10.1159/000177285 Abstract The effects of dietary gamma-linolenic acid supplementation in the form of evening primrose oil were examined in pregnant zinc-deficient rats and subsequently in their newborn pups. This supplementation was beneficial, since it reduced pup mortality, increased mean litter size and maintained appetite throughout two thirds of the gestation period. Consequently, gamma-linolenic acid seems to correct some of the biological effects of zinc deficiency. It is suggested that evening primrose oil could be used in cases of zinc deficiency caused by metabolic disturbances. Effects of gamma-linolenic acid supplementation on pregnant rats fed a zinc-deficient diet Ann Nutr Metab. 1987;31(5):312-9. https://pubmed.ncbi.nlm.nih.gov/2821872/

75. A double-blind trial of essential fatty acid supplementation in patients with tardive dyskinesia Psychiatry Res. 1989 Mar;27(3):313-23. https://pubmed.ncbi.nlm.nih.gov/2565585/ K S Vaddadi 1 , P Courtney, C J Gilleard, M S Manku, D F Horrobin PMID: 2565585 DOI: 10.1016/0165-1781(89)90146-7 Abstract This study reports the results of a trial of essential fatty acid (EFA) supplementation in psychiatric patients (predominantly schizophrenics) with movement disorders. Evidence of EFA deficiency in these patients was observed. The antidyskinetic effect of EFA supplementation was marginally significant but not clinically important. However, active treatment produced highly significant improvements in total psychopathology scores and schizophrenia subscale scores, and a significant improvement in memory. Methods Subjects and Drugs. We undertook a controlled trial of EFA supplementation in the form of Efamol capsules, each capsule containing 72% linoleic acid and 9% y-linolenic acid, in psychiatric patients with established movement disorders who had been exposed to neuroleptics over a long period of time…

76. [Action of evening primrose oil on cardiovascular risk factors in insulin-dependent diabetics] Clin Ter. 1989 Jun 15;129(5):381-8. https://pubmed.ncbi.nlm.nih.gov/2548804/ [Article in Italian] R Uccella, A Contini, M Sartorio PMID: 2548804 Abstract In an open study, the authors compared two groups of insulin-dependent diabetics matched for age and metabolic control, one of which was given a linoleic-gamma-linolenic acid mixture (3 g daily), the other served as control. The effect, attributed to gamma- linolenic acid only, was evaluated as explained in the text and is shown in the table. At the end of two months no change was found in the control group while favorable changes of HDL-cholesterol and platelet adhesiveness were observed in the experimental group.

77. Essential fatty acid treatment--effects on nerve conduction, polyol pathway and axonal transport in streptozotocin diabetic rats Diabetologia. 1989 Sep;32(9):655-9.doi: 10.1007/BF00274252 https://pubmed.ncbi.nlm.nih.gov/2477293/ D R Tomlinson 1 , J P Robinson, A M Compton, P Keen PMID: 2477293 DOI: 10.1007/BF00274252 Abstract: This study was designed to examine the effect of dietary supplementation with essential fatty acids (evening primrose oil--5% weight: weight added to the diet) on acute neurophysiological and neurochemical defects in streptozotocin-diabetic rats. Diabetic rats, which were not given evening primrose oil, showed highly significant elevations of nerve sorbitol and fructose combined with a depletion of nerve myo-inositol. In those animals there was also a 40% reduction (p less than 0.02) in the accumulation of axonally transported substance P-like immunoreactivity proximal to a 12 h sciatic nerve ligature together with reduced motor nerve conduction velocity (13% [p less than 0.001] and 20% [p less than 0.001] in two separate experiments). Treatment of other diabetic rats with evening primrose oil prevented completely the development of the motor nerve conduction velocity deficit without affecting sorbitol, fructose or myo-inositol levels or the deficit in axonal transport of substance P. In a second experiment, treatment of diabetic rats with evening primrose oil was associated with significant attenuation of the conduction velocity deficit, but not complete prevention.

78. G A Jamal 1 , H Carmichael PMID: 2159860 DOI: 10.1111/j.1464-5491.1990.tb01397.x Abstract Twenty-two patients with distal diabetic polyneuropathy confirmed both clinically and by objective nerve function studies, completed a double-blind, placebo-controlled study to assess the effect of dietary supplementation with gamma-linolenic acid on their neuropathy. Patients received either 360 mg gamma-linolenic acid (12 patients) or indistinguishable placebo capsules (10 patients) for 6 months. All patients were assessed at the beginning and end of the study period by neuropathy symptom and sign scoring, motor and sensory nerve conduction studies, and thermal threshold measurements. When compared with the placebo group, patients on gamma-linolenic acid showed statistically significant improvement in neuropathy symptom scores (p less than 0.001), median nerve motor conduction velocity (p less than 0.01) and compound muscle action potential amplitude (p less than 0.01), peroneal nerve motor conduction velocity (p less than 0.05) and compound muscle action potential amplitude (p less than 0.05), median (p less than 0.01) and sural (p less than 0.001) sensory nerve action potential amplitude and ankle heat threshold (p less than 0.001) and cold threshold (p less than 0.01) values. gamma-Linolenic acid therapy might have a useful role in the prevention and treatment of distal diabetic polyneuropathy. The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial Diabet Med. 1990 May;7(4):319-23. https://pubmed.ncbi.nlm.nih.gov/2159860/

79. N S Gardiner 1 , J R Duncan PMID: 1650000 DOI: 10.1016/0952-3278(91)90149-y Abstract This study examined the effects of linoleic acid (LA) and gamma-linolenic acid (GLA) on BL6 melanoma growth in cell culture and of safflower oil (SFO) which contains LA and evening primrose oil (EPO) which contains GLA, on melanoma growth when grown in mice. The delta-6-desaturase activity of the melanoma cells in the two systems was also examined and an attempt made to relate the activity of the enzyme to the effects of GLA on cell and tumour growth. LA and GLA were found to be equipotent in inhibiting growth of the in vitro cultured BL6 cells which were found to contain an appreciable level of delta-6-desaturase activity. EPO was however found to be a more potent promoter of in vivo melanoma growth in mice than SFO. Melanomas grown in mice were found to lack delta-6-desaturase activity suggesting that the EPO diet, by providing GLA, was able to compensate for the loss of enzyme activity in the melanomas. The possibility that melanomas in mice have a requirement for GLA for growth while in in vitro cultured cells excess GLA inhibits the growth of the cells through an increase in lipid peroxidation is discussed. Possible involvement of delta-6-desaturase in control of melanoma growth by gamma-linolenic acid Prostaglandins Leukot Essent Fatty Acids. 1991 Mar;42(3):149-53. https://pubmed.ncbi.nlm.nih.gov/1650000/

80. P L Biagi 1 , A Bordoni, S Hrelia, M Celadon, D F Horrobin PMID: 1674661 DOI: 10.1016/0005-2760(91)90041-f Abstract We have recently demonstrated that in rats the process of delta 6-desaturation of linoleic and alpha-linolenic acids slows with aging. One method of counteracting the effect of slowed desaturation of linoleic acid would be to provide the 6-desaturated metabolite, gamma- linolenic acid (18:3(n-6) GLA) directly. We have here investigated the 6-desaturation of both linoleic and alpha-linolenic acids in liver microsomes of young and old rats given GLA in the form of evening primrose oil (EPO) (B diet) in comparison to animals given soy bean oil alone (A diet), monitoring also the fatty acid composition of liver microsomes and relating this to the microviscosity of the membranes. In young rats the different experimental diets did not produce any difference in delta 6-desaturase (D6D) activity on either substrate suggesting that, when D6D activity is at or near its peak, the variations in diet tested are unable to influence it. In the old animals the rate of 6- desaturation of linoleic and particularly of alpha-linolenic acid was significantly greater in the B diet fed animals than in the A diet fed. The effects of the diets on the fatty acid composition of liver microsomes were consistent with the findings with regard to 6-desaturation. Administration of GLA partially corrected the abnormalities of n-6 essential fatty acid (EFA) metabolism by raising the concentration of 20:4(n-6) and other 6-desaturated EFAs. Furthermore, the GLA rich diet also increased the levels of dihomo-gamma-linolenic acid and of 6- desaturated n-3 EFAs in the liver microsomes. The microviscosity of microsomal membranes as indicated by DPH polarization was correlated with the unsaturation index of the same membranes. There was a very strong correlation between the two. In both young and old rats the B diet reduced the microviscosity and increased the unsaturation index. However, the effect was much greater in the old animals. Gamma-linolenic acid dietary supplementation can reverse the aginginfluenceonratlivermicrosomedelta6-desaturaseactivity. Biochim Biophys Acta. 1991 May 8;1083(2):187-92. https://pubmed.ncbi.nlm.nih.gov/1674661/

81. A Cant 1 , J Shay, D F Horrobin PMID: 1668100 DOI: 10.3177/jnsv.37.573 Abstract Total fat content and therefore total energy content and the content of essential fatty acids (EFAs) in milk are known to decline with prolonged breast feeding. In a placebo-controlled study a variety of evening primrose oil (Efamol) rich in linoleic and gamma-linolenic acids, or a matching placebo were given to 39 women for a period of 8 months starting between the 2nd and 6th months of lactation. Total fat and EFA contents of the milk declined in the placebo group but rose in the primrose oil supplemented group. A surprisingly high proportion of the supplemented dietary fatty acids could be accounted for by appearance in the milk. The milk composition can be readily manipulated by changing the fatty acid composition of the maternal diet. The effect of maternal supplementation with linoleic and gamma-linolenic acids on the fat composition and content of human milk: a placebo-controlled trial J Nutr Sci Vitaminol (Tokyo). 1991 Dec;37(6):573-9. https://pubmed.ncbi.nlm.nih.gov/1668100/

82. B B Oon 1 , D Muggleston, A Warley PMID: 1543584 DOI: 10.1113/expphysiol.1992.sp003572 Abstract Blood glucose, circulating lymphocyte numbers, and the percentage of T- and B-lymphocytes were measured in diabetic and non-diabetic rats which had been fed on control diets, or diets which included oil of evening primrose or coconut oil. In diabetic animals fed on the control or coconut oil diet the number of circulating lymphocytes decreased; this was caused by a decrease in both T- and B-lymphocytes. The decreases in lymphocyte numbers was less in the diabetic animals fed on the diet enriched in evening primrose oil. In these animals the decrease in T-lymphocytes was less and the percentage of B-lymphocytes was increased. It is suggested that the diet enriched in evening primrose oil exerts its protective effect by providing gamma-linolenic acid which is necessary for biosynthesis of prostaglandin E1. A diet enriched in essential fatty acids protects against the loss of lymphocytes which occurs in rats suffering from streptozotocin-induced diabetes Exp Physiol. 1992 Jan;77(1):185-90. https://pubmed.ncbi.nlm.nih.gov/1543584/

83. G Ramesh 1 , U N Das, R Koratkar, M Padma, P S Sagar PMID: 1330107 Abstract An earlier study showed that essential fatty acids and their metabolites can kill tumor cells in vitro. This tumoricidal action can be correlated to an increase in generation of free radicals in the tumor cells. Evening primrose oil (EPO) is a rich source of linoleic acid and gamma-linolenic acid. We report that EPO can kill tumor cells both in vitro and in vivo. This tumoricidal action of EPO was associated with a threefold increase in superoxide generation. One of the factors that is capable of interfering with the cytotoxic action of fatty acids appears to be the protein content of the medium. Fatty acids can bind to protein and thus prevent their cytotoxic action. Effect of essential fatty acids on tumor cells Nutrition. Sep-Oct 1992;8(5):343-7. https://pubmed.ncbi.nlm.nih.gov/1330107/

84. D F Horrobin 1Affiliations PMID: 8380930 DOI: 10.1016/0952-3278(93)90016-p Abstract Gamma-linolenic acid (GLA) has recently been found to be beneficial in the management of breast pain and of diabetic neuropathy. GLA is a precursor of unsaturated fatty acids which are important in membrane structures, as second messengers in their own right and as precursors of eicosanoids. While the mechanisms of GLA action are likely to be complex, non-eicosanoid effects are probably of substantial importance. These effects include modification of membrane fluidity and of the functions of lipid-associated receptors and changes in the inositol cycle. The effects of gamma-linolenic acid on breast pain and diabetic neuropathy: possible non-eicosanoid mechanisms Prostaglandins Leukot Essent Fatty Acids. 1993 Jan;48(1):101-4. https://pubmed.ncbi.nlm.nih.gov/8380930/

85. P C Calder 1Affiliations PMID: 8298526 Abstract 1. Lymphocytes play an important role in cell-mediated immunity and have been implicated in inflammatory and autoimmune diseases. 2. Unsaturated fatty acids, including oleic, linoleic, alpha-linolenic, arachidonic, eicosapentaenoic and docosahexaenoic acids, inhibit mitogen-stimulated lymphocyte proliferation in vitro. The inhibition of proliferation is dependent upon the concentration of fatty acid, the time during culture of fatty acid addition, the duration of exposure of the cells to the fatty acid and the chain length and degree of unsaturation of the fatty acid. 3. Unsaturated fatty acids suppress production of the immunoregulatory cytokine interleukin-2 by lymphocytes in vitro. 4. Triacylglycerols containing unsaturated fatty acids inhibit lymphocyte proliferation and natural killer cell activity in vitro. 5. Feeding weanling rats diets containing olive oil, evening primrose oil or fish oil results in suppression of lymphocyte proliferation. 6. Preliminary studies indicated that supplementation of the diet of healthy humans with fish oil-containing capsules suppresses lymphocyte proliferation and interleukin-2 production. 7. These effects, along with inhibitory effects upon the functions of other cells involved in the immune response, in particular monocytes and macrophages, indicate that certain unsaturated fatty acid-containing oils (particularly evening primrose oil and fish oil) may be of benefit in the treatment of inflammatory and autoimmune diseases. The effects of fatty acids on lymphocyte functions Braz J Med Biol Res. 1993 Sep;26(9):901-17. https://pubmed.ncbi.nlm.nih.gov/8298526/

86. [Influence of evening primrose oil on blood pressure and the pressor response to angiotensin II in pregnant and non-pregnant rabbits] Ginekol Pol. 1994 Mar;65(3):111-4. [Article in Polish] M Zieliński 1 , L Wojnarski, Z Celewicz, A Cretti PMID: 8001843 Abstract Evening primrose oil was given through a intragastric catheter in dose of 50 mg/kg day for 10 days to pregnant (8 animals) and nonpregnant (8 animals) rabbits. Control groups contained 8 pregnant and 8 nonpregnant animals. In the acute experiment we estimated directly (intraarterially) basal blood pressure and pressor response to angiotensin II (A II). The systolic and diastolic response to A II was significantly lower in pregnant rabbits which received evening primrose oil compared to control group. No significant effect was found in the nonpregnant groups. Basal (before A II) systolic and diastolic blood pressure did not differ between the treated and untreated subject in each group. https://pubmed.ncbi.nlm.nih.gov/8001843/

87. The effect of gamma-linolenic acid on clinical status, red cell fatty acid composition and membrane microviscosity in infants with atopic dermatitis Drugs Exp Clin Res. 1994;20(2):77-84. https://pubmed.ncbi.nlm.nih.gov/7924900/ P L Biagi 1 , A Bordoni, S Hrelia, M Celadon, G P Ricci, V Cannella, A Patrizi, F Specchia, M Masi PMID: 7924900 Abstract A double blind placebo-controlled study of two doses of gamma-linolenic acid, provided by evening primrose oil (EPO, Epogam, Searle, U.K.), in children with atopic dermatitis was performed: 1) to examine the effect of gamma-linolenic acid administration on the clinical status of children with atopic dermatitis and abnormalities of IgE-mediated immune responses compared to those without such IgE abnormalities; 2) to investigate the effect of gamma-linolenic acid on red cell fatty acid composition and 3) to assess whether treatment with gamma-linolenic acid induced changes in red cell membrane microviscosity. A significant improvement in the overall severity of the clinical condition was seen in children treated with gamma-linolenic acid, independent of whether the children had manifestations of IgE-mediated allergy. Furthermore, gamma-linolenic acid treatment increased the percentage content of n-6 fatty acids in erythrocyte cell membrane; this increase was more marked in the membranes of children treated with high doses of EPO. In the high dose group a significant increase in dihomogamma-linolenic acid (DGLA) occurred. This may be of particular relevance because of the potential importance of DGLA as a precursor of antiinflammatory prostanoids. Red cell membrane microviscosity did not change in any group after treatment with EPO, even in high doses, despite a significant increase in the proportion of long chain polyunsaturated fatty acids.

88. Effects of anti-oxidant treatment on sciatic nerve dysfunction in streptozotocin-diabetic rats; comparison with essential fatty acids Diabetologia. 1995 Feb;38(2):129-34. https://pubmed.ncbi.nlm.nih.gov/7713308/ C Karasu 1 , M Dewhurst, E J Stevens, D R Tomlinson PMID: 7713308 DOI: 10.1007/BF00400086 Abstract In Study 1, the effects of treatment of streptozotocin-diabetic rats with the antioxidants, probucol or vitamin E were compared. Untreated diabetic rats showed a reduction of 45% (p < 0.01) in nerve laser Doppler flux, which was used as an index of nerve blood flow. In diabetic rats treated with either probucol or vitamin E nerve Doppler flux was reduced by only 13 or 16%, respectively (p < 0.01 for either compared to untreated diabetic rats). A second study examined the effects of treatment with evening primrose oil either alone or in combination with probucol. Reduced nerve Doppler flux was reproduced in untreated diabetic rats (47%; p < 0.01). In parallel diabetic groups, nerve Doppler flux was reduced by only 14% with evening primrose oil alone and by 8% with evening primrose oil plus probucol (both p < 0.01 vs untreated diabetic rats). Both treatments were also associated with marked attenuation of motor and sensory nerve conduction velocity deficits. Measurements on plasma from rats showed normalisation of triglyceride levels by probucol treatment without an effect on those of cholesterol in Study 1. In Study 2, the converse was true for evening primrose oil treatment, whilst the combined treatment lowered both plasma triglycerides and cholesterol. This work indicates similar effects of antioxidants and evening primrose oil against reduced nerve Doppler flux and conduction velocity in diabetic rats, with dissimilar actions on plasma triglycerides and cholesterol.

89. Comparison of the effects of ascorbyl gamma-linolenic acid and gamma- linolenic acid in the correction of neurovascular deficits in diabetic rats Diabetologia. 1996 Sep;39(9):1047-54. https://pubmed.ncbi.nlm.nih.gov/8877288/ N E Cameron 1 , M A Cotter PMID: 8877288 DOI: 10.1007/BF00400653 Abstract Essential fatty acid metabolism is impaired by diabetes mellitus and gamma-linolenic acid rich treatments such as evening primrose oil correct deficits in nerve conduction and endoneurial blood flow in diabetic rats. Other mechanistically unrelated treatments, such as antioxidants and aldose reductase inhibitors have a similar effect and there may be positive interactions with multiple treatments. Our aim was to compare the efficacy of a novel essential fatty acid derivative, ascorbyl gamma-linolenic acid, with that of gamma-linolenic acid in correcting diabetic neurovascular deficits. Eight weeks of diabetes caused 20.4 and 48.2% reductions in sciatic motor conduction velocity and nutritive endoneurial blood flow, respectively. Treatment was given for the last 2 weeks with gamma-linolenic acid (100 mg.kg-1.day-1) either in pure form or as ascorbyl gamma-linolenic acid, an equivalent dose of ascorbate (21 mg.kg-1.day-1) or jointly with ascorbate and gamma-linolenic acid. Conduction velocity was corrected by 39.8, 87.4, 13.2 and 66.8% with gamma-linolenic acid, ascorbyl gamma-linolenic acid, ascorbate and gamma-linolenic acid plus ascorbate, respectively. Corresponding ameliorations of the nutritive blood flow deficit were 44.0, 87.4, 87.4, 13.2 and 65.7%. For the gamma-linolenic acid plus ascorbate combinatin, and especially for ascorbyl gamma-linolenic acid, the magnitude of correction for conduction velocity and blood flow was greater than expected for simple addition of ascorbate and gamma- linolenic acid, indicating a synergistic interaction. Thus, with an efficacy 40 times that of evening primrose oil in rats, ascorbyl gamma-linolenic acid may be a suitable candidate for clinical trials of diabetic neuropathy.

90. Effects of dietary supplementation with arachidonic acid rich oils on nerve conduction and blood flow in streptozotocin-diabetic rats Prostaglandins Leukot Essent Fatty Acids. 1997 May;56(5):337-43. https://pubmed.ncbi.nlm.nih.gov/9175169/ M A Cotter 1 , N E Cameron PMID: 9175169 DOI: 10.1016/s0952-3278(97)90581-0 Abstract Diabetes mellitus is associated with defective essential fatty acid desaturation. In experimental models this contributes to characteristic reductions in peripheral nerve conduction velocity (NCV) and blood flow, which may be corrected by dietary supplementation with gamma-linolenic acid (GLA) rich oils to bypass the delta-6 desaturation deficit. There is debate about the mechanism of this improvement, including whether it depends on synthesis of series 1 prostanoids derived from di-homo GLA or series 2 prostanoids from arachidonic acid (ARA). The aim was to assess the efficacy of two ARA-rich (approximately 39% content) oils in correcting neurovascular dysfunction in streptozotocin-induced diabetic rats. After 6 weeks of untreated diabetes, rats were treated for a further 2 weeks with 1% dietary oil supplements before assessment of sciatic motor NCV and endoneurial blood flow. NCV was 19% reduced in diabetic rats and this was largely (approximately 86%) corrected by both oil treatments. A 48% deficit in endoneurial nutritive blood flow with diabetes was approximately 70% reversed by the two oils, vascular conductance being in the non-diabetic range. Thus, nerve conduction and perfusion deficits in diabetic rats are corrected by ARA-rich oil treatment. The magnitudes of these changes were similar to expectations based on previous studies of GLA-rich oils, therefore it is likely that the neurovascular effect of increased synthesis of series 2 prostanoids makes a major contribution to the beneficial action of n-6 essential fatty acids in experimental diabetic neuropathy.

91. Differential effects of dietary Oenothera, Zizyphus mistol, and corn oils, and essential fatty acid deficiency on the progression of a murine mammary gland adenocarcinoma Nutrition. 1999 Mar;15(3):208-12. https://pubmed.ncbi.nlm.nih.gov/10198915/ S E Muñoz 1 , M Piegari, C A Guzmán, A R Eynard PMID: 10198915 DOI: 10.1016/s0899-9007(98)00181-6 Abstract The modulating effect of dietary enrichment in mistol seed oil (MO) containing 25% of alpha-linolenic acid (ALA), evening primrose oil (EPO) enriched in gamma-linolenic acid (GLA) and corn oil (CO) as sources of omega-6 and omega-9 fatty acids on the growth parameters of one transplantable mammary tumor were compared. Mice fed on different lipid formulae were inoculated with a mammary gland adenocarcinoma and different growth development tumor parameters were recorded. Results showed that corn oil feeding slowed down most of the tumor growth parameters, as did the EPO diet. MO also showed antitumor activity. Olein feeding, which induces an essential fatty acid deficiency (EFAD), increased the incidence and the multiplicity of metastases when compared with the controls. It may be concluded that a diet enriched in omega-6 fatty acids did not behave as a tumor promoter in this mammary gland tumor model. The antitumor activities of EPO and MO are corroborated in present experiments, suggesting that both oils may be of value in nutritional approaches of mammary gland tumor therapies. In addition, present data add further experimental proof about the proposed protumorigenic proneness induced by the EFAD state.

92. Cytokine levels affected by gamma-linolenic acid Prostaglandins Leukot Essent Fatty Acids. 1998 Oct;59(4):273-7. https://pubmed.ncbi.nlm.nih.gov/9849654/ J Dirks 1 , C H van Aswegen, D J du Plessis PMID: 9849654 DOI: 10.1016/s0952-3278(98)90141-7 Abstract This study was undertaken to assess whether gamma-linolenic acid (GLA) in the form of evening primrose oil (EPO) could affect rat serum cytokines, interferon-gamma (IFN-gamma), monocyte chemotactic protein-1 (MCP-1) and tumour necrosis factor-alpha (TNF-alpha). The following diets were administered: control, glucan, Freund's adjuvant and glucan plus Freund's adjuvant with and without GLA. In the presence of GLA, the IFN-gamma and MCP-1 levels were significantly decreased in contrast to the control group of TNF-alpha, which was significantly stimulated. On account of interaction between diets and GLA, the remaining diet groups of TNF- alpha were either not affected or were inhibited in the presence of GLA. The observations indicate that GLA may modulate the level of serum IFN-gamma, MCP-1 and TNF-alpha, which may be a worthwhile line of treatment in certain human diseases.

93. Gamma-linolenic acid provides additional protection against ventricular fibrillation in aged rats fed linoleic acid rich diets Prostaglandins Leukot Essent Fatty Acids. 2000 Feb;62(2):129-34. https://pubmed.ncbi.nlm.nih.gov/10780878/ J S Charnock PMID: 10780878 DOI: 10.1054/plef.1999.0132 Abstract Ligation of the coronary artery in rats produces severe ventricular fibrillation (VF) and malignant cardiac arrhythmia. Mortality increases with the age of the animal. Diets rich in saturated fatty acids (SF) but low in linoleic acid (LA) increase, but diets high in LA and low in SF decrease the severity of VF and mortality in older animals. The effects of an LA enriched diet can be blocked by inhibition of cyclooxygenase suggesting that conversion of LA to eicosanoids is central to the development of VF. Conversion of LA to gamma-linolenic acid (GLA) via delta-6 desaturase is the first step in the process. The activity of delta-6 desaturase declines with age. Thus inclusion of GLA in the diet of older animals may provide an additional benefit over LA alone. Dietary supplements of evening primrose oil (EPO) to one year old rats reduced ischaemic VF more than a supplement of sunflower seed oil (SSO) without GLA. Substitution of borage oil (more GLA than EPO but less LA than either EPO or SSO) was without additional benefit.

94. The effect of gamma-linolenic acid on plasma and membrane lipids and renal prostaglandin synthesis in older subjects Bratisl Lek Listy. 2002;103(3):101-7. https://pubmed.ncbi.nlm.nih.gov/12190041/ A Hornych 1 , S Oravec, F Girault, B Forette, D F Horrobin PMID: 12190041 Abstract Senescence is associated with a decreased activity of enzyme delta-6 desaturase, which converts linoleic acid to gamma-linolenic acid. This enzymatic defect may alter the composition of plasma and membrane lipids, and influences the biosynthesis of renal prostaglandins. Exogenous supplementation of GLA during 3 months increases the plasma level of dihomo-gamma-linolenic acid (p < 0.002), and to a smaller degree, the level in erythrocyte membrane lipids. This treatment was associated with a beneficial reduction of cardiovascular risk factors (arterial hypertension, total cholesterol, apolipoprotein B, HDL-cholesterol, apolipoprotein A-I) and the renal function has become stable reached. Epogam treatment also increased the biosynthesis of renal prostaglandins, especially that of prostaglandin E2, which has a vasodilatory effect on vessel walls and reduces the elevated blood pressure. Conclusion: Dietary supplementation of essential fatty acids such as gamma-linolenic acid to old subjects has beneficial effect on their health condition. (Tab. 6, Fig. 5, Ref. 37.)

95. Botanicals and dietary supplements in diabetic peripheral neuropathy J Am Board Fam Pract . Jan-Feb 2003;16(1):47-57.doi: 10.3122/jabfm.16.1.47. https://pubmed.ncbi.nlm.nih.gov/12583650/ PMID: 12583650 DOI: 10.3122/jabfm.16.1.47 Kathleen M Halat 1 , Cathi E Dennehy Abstract Background: Many persons use botanicals and dietary supplements for chronic conditions that do not respond to traditional Western medications. Tricyclic antidepressants, a common treatment option for diabetic neuropathy, can have many side effects and are a poor choice in certain populations (eg, the elderly). As such, patients might turn to botanicals and dietary supplements, not realizing that these products are not well regulated. Methods: This article reviews botanicals and dietary supplements that have been involved in randomized controlled trials (RCTs) for diabetic neuropathy. We searched MEDLINE for English-language literature dating from 1966 to April 2001 using the following subject headings: (1) diabetes and botanical, herb, and supplement, (2) neuropathy and botanical, herb, and supplement, and (3) diabetic neuropathy and botanical, herb, and supplement. Results: Our search found agents that might improve symptoms of neuropathy (eg, evening primrose oil, alpha-lipoic acid, capsaicin) without affecting glucose control. Botanicals and dietary supplements involved in only one RCT or associated with little clinical benefit were reviewed in brief. Conclusions: Evening primrose oil, alpha-lipoic acid, and capsaicin have received the greatest attention for their use in diabetic neuropathy, but further studies are needed to confirm their efficacy. Patients using these products need to be informed of potential drug interactions and side effects.

96. Effects of different dietary oils on inflammatory mediator generation and fatty acid composition in rat neutrophils Metabolism. 2004 Jan;53(1):59-65. https://pubmed.ncbi.nlm.nih.gov/14681843/ R de La Puerta Vázquez 1 , E Martínez-Domínguez, J Sánchez Perona, V Ruiz-Gutiérrez PMID: 14681843 DOI: 10.1016/j.metabol.2003.08.010 Abstract Virgin olive oil (VOO) compared with fish oil (FO) and evening primrose oil (PO) on the ability of stimulated leukocytes to produce inflammatory mediators was investigated in rats. Weaned Wistar rats were fed a basal diet (BD) (2% by weight of corn oil) or diets containing 15% by weight of VOO, PO, or FO. After 8 weeks, glycogen-elicited peritoneal polymorphonuclear leukocytes, mainly neutrophils, were isolated. The calcium-ionophore stimulated neutrophils (2.5 x 10(6) cells/mL) obtained from rats fed the different oils produced a higher release of lysosomal enzymes (beta-glucuronidase, lysozyme, and myeloperoxidase [MPO]) compared with those fed BD. The production of reactive oxygen species (ROS) in response to the stimulant, 12-O-tetradecanoyl-phorbol-13- acetate (TPA), by neutrophils from the VOO group (15.44 nmol of O(2)(-) and 6.56 nmol of H(2)O(2)) was similar to the BD group (12.01 nmol O(2)(-) and 8.49 nmol H(2)O(2)) and significantly lower than the PO (20.90 nmol O(2)(-) and 10.84 nmol H(2)O(2)) and FO (20.93 nmol O(2)(-) and 12.79 nmol H(2)O(2)) groups. The cyclooxygenase-derived eicosanoid production was reduced by the lipid enrichment of the diets. Whereas the generation of prostaglandin E(2) (PGE(2)) was significantly decreased in VOO (5.40 ng/mL), PO (4.95 ng/mL), and FO (1.44 ng/mL) groups compared with BD (8.19 ng/mL), thromboxane B(2) (TXB(2)) reduction was especially significant in neutrophils from the FO diet group (14.67 ng/mL compared with 26.69 ng/mL from BD). These experimental data suggest that FO and PO, as well as VOO, could be considered a valuable strategy in preventing the generation of some inflammatory mediators.

97. Prevention and partial reversal of diabetes-induced changes in enteric nerves of the rat ileum by combined treatment with alpha-lipoic acid and evening primrose oil Auton Neurosci. 2004 Mar 31;111(1):57-65. https://pubmed.ncbi.nlm.nih.gov/15109939/ Hannah R Shotton 1 , Steven Broadbent, Jill Lincoln PMID: 15109939 DOI: 10.1016/j.autneu.2004.02.004 Abstract Treatment with alpha-lipoic acid (LA) or evening primrose oil (EPO), individually, fails to prevent diabetes-induced changes in enteric nerves. Since synergy between these treatments has been reported, the aim was to investigate the effectiveness of combined LA/EPO treatment. LA and EPO were administered in the diet (approximately 80 and 200 mg/kg/day, respectively) to control and diabetic (induced by streptozotocin, 65 mg/kg, i.p.) rats. For prevention, treatment started after 1 week and lasted 7 weeks. For reversal, treatment lasted 4 weeks and was initiated after 8 weeks. Nerves supplying the ileum containing vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and noradrenaline (NA) were examined immunohistochemically or biochemically. Diabetes caused a significant increase in VIP-containing cell bodies (p<0.001), decrease in NA content (p<0.01) and loss of CGRP- immunoreactivity. LA/EPO treatment totally prevented diabetes-induced changes in VIP (p<0.001) and CGRP and partially reversed (p<0.05) these changes once they had been allowed to develop. In contrast, treatment had no effect on diabetes-induced changes in NA-containing nerves. Therefore, LA and EPO are only effective at treating diabetes-induced changes in some enteric nerves when administered in combination. However, diabetes-induced changes in NA-containing nerves are resistant to treatment.

98. A 5-month open study with long-chain polyunsaturated fatty acids in dyslexia J Med Food. 2007 Dec;10(4):662-6. https://pubmed.ncbi.nlm.nih.gov/18158838/ Lars Lindmark 1 , Peter Clough PMID: 18158838 DOI: 10.1089/jmf.2006.399 Abstract This open pilot study investigated effects of a docosahexaenoic acid (DHA)-rich supplement on learning ability in a group of 20 dyslexic children in Sweden. Children formally diagnosed as dyslexic took eight capsules per day of a long-chain polyunsaturated fatty acid (LC-PUFA) supplement containing high-DHA fish oil and evening primrose oil. Subjective assessments by the children and their parents were completed at baseline and 6, 12, and 20 weeks after supplementation. Quantitative evaluation by word-chain test was completed before and after 4 months of supplementation to measure word decoding (speed of reading) and letter decoding (motoric-perceptual speed). Subjective parent and child assessments showed increasing numbers of positive responders over time in reading speed, general schoolwork, and overall perceived benefit. Significant improvements were observed in reading speed and motor-perceptual velocity. Thirteen of 17 children had a significant improvement on the word-chain test (P < .04). Reading speed improved by 60% from 1.76 +/- 0.29 before the study to 2.82 +/- 0.36 after supplementation (P < .01 by Wilcoxon sign test). Motoric-perceptual velocity improved by 23% from a stanine value of 3.76 +/- 0.42 to 4.65 +/- 0.66 after supplementation (P < .05 by Wilcoxon sign test). Thus LC-PUFA supplementation for 5 months provides positive and clear beneficial effect on variables usually impaired by dyslexia.

99. Oral omega-6 essential fatty acid treatment in contact lens associated dry eye Cont Lens Anterior Eye. 2008 Jun;31(3):141-6; quiz 170. Epub 2008 Mar 4. https://pubmed.ncbi.nlm.nih.gov/18313350/ Karolien H Kokke 1 , Judith A Morris, John G Lawrenson PMID: 18313350 DOI: 10.1016/j.clae.2007.12.001 Abstract Purpose: Symptoms of dry eye are commonly reported in contact lens wearers and are a frequent cause of non-tolerance. The purpose of the present study is to evaluate the effects of oral treatment with particular omega-6 fatty acids in the form of evening primrose oil (EPO) on subjective symptoms, ocular surface signs and tear film characteristic in patients with contact lens associated dry eye. Methods: The study design was randomised, double-masked and placebo controlled. 76 female soft contact lens wearers were treated for 6 months with either EPO or placebo (olive oil). Subjects underwent three examinations (baseline, 3 and 6 months). At each examination subjects were given a questionnaire relating to lens comfort and dry eye symptoms and underwent a series of tests of tear film characteristics (tear meniscus height, break-up time), meibomian gland function (lipid layer thickness and quality) and ocular surface parameters (hyperaemia and staining). Results: The EPO group showed a significant improvement in the specific symptom of 'dryness' at 3 and 6 months (p<0.01) and also a significant improvement in overall lens comfort at 6 months (p<0.01). Tear meniscus height was increased in the EPO group at 6 months relative to baseline (p<0.01), although all other objective signs were unchanged. Conclusion: This study provides evidence for a beneficial effect of particular orally administered omega-6 fatty acids in alleviating dry eye symptoms and improving overall lens comfort in patients suffering from contact lens associated dry eye.

100. Femicomfort in the treatment of premenstrual syndromes: a double-blind, randomized and placebo-controlled trial Iran J Psychiatry. Spring 2010;5(2):47-50. https://pubmed.ncbi.nlm.nih.gov/22952490/ Ladan Kashani 1 , Nafiseh Saedi, Shahin Akhondzadeh PMID: 22952490 PMCID: PMC3430493 Abstract Objective: Premenstrual syndromes (PMS) affecting 20-40% of women of reproductive age. The aim of this double blind and placebo controlled trial was to investigate whether femicofort a supplement contains Vitamin B6, Vitamin E and evening primrose oil could relieve symptoms of PMS. Method: This was a randomized and double blind clinical trial. The trial was conducted between November 2009 and April March 2010. Women aged 20 to 45 years with regular menstrual cycles and experience of PMS symptoms (According to the current diagnostic criteria proposed by the American College of Obstetrics and Gynecology) for at least 6 months were eligible for the study. Patients were randomized to receive femicomfort or placebo in a 1: 1 ratio using a computer-generated code. The assignments were kept in sealed, opaque envelopes until the point of analysis of data. In this double-blind, patients were randomly assigned to receive capsule of femicomfort (Group A) or capsule placebo for two menstrual cycles (cycles 3 and 4). The primary outcome measure was the Daily Symptom Report, a checklist of 17 premenstrual symptoms rated from 0 to 4 according to their severity throughout the menstrual cycle. Secondary outcome measure was Hamilton Depression Rating Scale (17-item). Results: Femicomfort at this dose was found to be effective in relieving symptoms of PMS. The difference between the femicomfort and placebo in the frequency of side effects was not significant. Conclusion: The results of this study indicate the efficacy of femicomfort in the treatment of PMS.

101. Herbal therapy for treating rheumatoid arthritis Cochrane Database Syst Rev. 2011 Feb 16;(2):CD002948. https://pubmed.ncbi.nlm.nih.gov/21328257/ Melainie Cameron 1 , Joel J Gagnier, Sigrun Chrubasik PMID: 21328257 DOI: 10.1002/14651858.CD002948.pub2 Abstract Background: Herbal medicine interventions have been identified as having potential benefit in the treatment of rheumatoid arthritis (RA). Objectives: To update an existing systematic (Cochrane) review of herbal therapies in RA. Main results: Twelve new studies were added to the update, a total of 22 studies were included. Evidence from seven studies indicate potential benefits of gamma linolenic acid (GLA) from evening primrose oil, borage seed oil, or blackcurrent seed oil, in terms of reduced pain intensity (mean difference (MD) -32.83 points, 95% confidence interval (CI) -56.25 to -9.42,100 point pain scale); improved disability (MD -15.75% 95% CI - 27.06 to -4.44%); and an increase in adverse events (GLA 20% versus placebo 3%), that was not statistically different (relative risk 4.24, 95% CI 0.78 to 22.99). Three studies compared Tripterygium wilfordii (thunder god vine) to placebo and one to sulfasalazine and indicated improvements in some outcomes, but data could not be pooled due to differing interventions, comparisons and outcomes. One study reported serious side effects with oral Tripterygium wilfordii Hook F. In the follow-up studies, all side effects were mild to moderate and resolved after the intervention ceased. Two studies compared Phytodolor(®) N to placebo but poor reporting limited data extraction. The remaining studies each considered differing herbal interventions. Authors' conclusions: Several herbal interventions are inadequately justified by single studies or non-comparable studies in the treatment of rheumatoid arthritis. There is moderate evidence that oils containing GLA (evening primrose, borage, or blackcurrant seed oil) afford some benefit in relieving symptoms for RA, while evidence for Phytodolor® N is less convincing. Tripterygium wilfordii products may reduce some RA symptoms, however, oral use may be associated with several side effects. Many trials of herbal therapies are hampered by research design flaws and inadequate reporting. Further investigation of each herbal therapy is warranted, particularly via well designed, fully powered, confirmatory clinical trials that use American College of Rheumatology improvement criteria to measure outcomes and report results according to CONSORT guidelines.

102. Abstract Background: Atopic dermatitis (AD) is related to a deficiency of delta-6-desaturase, an enzyme responsible for converting linoleic acid to gamma-linolenic acid (GLA). Evening primrose oil (EPO) as a source of GLA has been of interest in the management of AD. Methods: FiftymildADpatientswithanEczema Area Severity Index(EASI) score of10orlesswere enrolledandrandomly dividedinto two groups. Thefirstgroup received anovalunmarked capsulecontaining450 mgofEPO(40 mgofGLA)percapsule,whileplacebo capsules identicalinappearanceandcontaining450 mgofsoybean oilwere giventotheother group.Treatment continuedforaperiod offour months. EASIscores, transepidermal waterloss(TEWL), andskinhydration were evaluatedinalltheADpatientsatthebaseline,andinmonths1,2,3, and4ofthestudy. Results: At the end of month 4, the patients of the EPO group showed a significant improvement in the EASI score (p=0.040), whereas the patients of the placebo group did not. There was a significant difference in the EASI score between the EPO and placebo groups (p=0.010). Although not statistically significant, the TEWL and skin hydration also slightly improved in the EPO patients group. Conclusion: We suggest that EPO is a safe and effective medicine for Korean patients with mild AD. Effect of Evening Primrose Oil on Korean Patients with Mild Atopic Dermatitis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Study Ann Dermatol. 2018 Aug;30(4):409-416. https://pubmed.ncbi.nlm.nih.gov/30065580/

103. Abstract Objective: The purpose of this study was to determine the efficacy and safety of evening primrose oil on women's psychological symptoms during menopause. Methods: A double-blinded randomized placebo-controlled trial carried out from September 2018 to February 2019 in Bandar Abbas, Iran. Eligible women randomly received either 1,000 mg of evening primrose oil capsules daily or matching placebo for 8 weeks. The Main outcome measures were psychological symptoms based on the psychological subscale of the Menopause Rating Scale. Independent samples t test was used for intergroup comparisons and paired samples t test for pre- and post-treatment comparisons. P ≤ 0.05 was considered statistically significant. Results: The 8-week treatment was completed by 189 women. The mean baseline psychological score did not differ among the two groups. After intervention, the psychological score, however, differed significantly among groups (P < 0.01). To distinguish the effect of evening primrose oil, we compared the reduction in the psychological score in each group. Regarding mean differences of the psychological score in both groups, there was a prominent alleviation in the intervention group mean difference: -3.44 (95% confidence interval of difference: -4.01 to -1.20) (P < 0.01). In addition, only one patient reported gastric upset in the intervention group. Conclusions: This study could provide evidence regarding the potential benefits of evening primrose oil for the psychological symptoms of postmenopausal women. Longer trials are necessary to make more reliable decisions about the use of evening primrose oil and its safety in clinical practice. Impact of evening primrose oil consumption on psychological symptoms of postmenopausal women: a randomized double- blinded placebo-controlled clinical trial Menopause 2020 Feb;27(2):194-198. https://pubmed.ncbi.nlm.nih.gov/31738736/

104. Abstract Background: Saturated fatty acid esters may cause mastalgia via hypersensitivity of breast epithelium to circulating hormones. Evening primrose oil (EPO) may restore the saturated/unsaturated fatty acid balance and decrease sensitivity to steroidal hormones or prolactin. Conflicting results exist regarding EPO treatment for mastalgia. The aim of this study was to determine the effectiveness of EPO and factors affecting its efficacy in treatment of mastalgia. Results: The therapeutic efficacy of EPO on mastalgia was significantly higher than with paracetamol (p < 0.001). Factors significantly affecting the efficacy of EPO treatment were hormone replacement therapy (HRT), IUD-with- levonorgestrel, iron deficiency, overt hypothyroidism, and Hashimoto thyroiditis (p < 0.01). Replacement of iron or thyroid hormone efficiently treated mastalgia in patients that did not respond to EPO treatment. Side effects (allergy, anxiety, blurred vision, constipation, and nausea) were rare and not statistically significant (p = 0.88). Conclusion: EPO can be used in the treatment of mastalgia without significant side effects. HRT, IUD-with- levonorgestrel, iron deficiency, overt hypothyroidism, and Hashimoto thyroiditis significantly affect the efficacy of EPO on mastalgia. Clinical Factors Affecting the Therapeutic Efficacy of Evening Primrose Oil on Mastalgia Ann Surg Oncol. 2020 Nov;27(12):4844-4852. https://pubmed.ncbi.nlm.nih.gov/32748152/

105. Abstract The mammalian target of rapamycin (mTOR) signaling plays a critical role in lipid synthesis and immune responses. The T regulatory cells (Treg) as suppressor of T cells, are a subset of T cells that modulate the immune system, maintain tolerance, and prevent autoimmune diseases.. The interleukin (IL) -10 derived from the Treg and T helper (Th) 2 is an anti-inflammatory cytokine in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Due to the exclusive roles of rapamycin (RAPA) in mTOR inhibition, we evaluated the regulatory effect of the hemp seed oil/evening primrose oil (HSO/EPO) supplement in comparison with RAPA in EAE. EAE was induced by using myelin oligodendrocyte glycoprotein peptide and complete freund's adjuvant (CFA) in C57BL/6 mice, total mRNA was extracted from local lymph nodes and real-time polymerase chain reaction was used to evaluate the expression level of the rapamycin-insensitive companion of mTOR complex 2 (RICTOR) and IL-10 genes. The expression of IL-10 and RICTOR genes were significantly increased in HSO/EPO group. In contrast with RAPA groups, histological findings have shown that the HSO/EPO treated group remarkably reduced cell infiltration and promoted remyelination. The EPO/HSO has beneficial effects on the repair of myelin, which was confirmed by immunological and histological findings. Regulatoryeffectsofhempseed/evening primroseoilsupplementincomparison withrapamycinontheexpression ofthemammaliantargetofrapamycin-complex 2 and interleukin-10 genes in experimental autoimmune encephalomyelitis Res Pharm Sci. 2019 Feb;14(1):36-45. https://pubmed.ncbi.nlm.nih.gov/30936931/

106. Abstract T helper (Th)-17 mediate inflammation in both peripheral tissues and the central nervous system. Signal transducer and activator of transcription factor3 (STAT3) is required for Th-cell pathogenicity and its activation in the brain has been demonstrated during the acute phase of experimental autoimmune encephalomyelitis (EAE) through the mammalian target of rapamycin (mTOR) signaling. Rapamycin (RAPA), an inhibitor of mTOR, can drive Forkhead box P3 (FOXP3+) induction as a regulatory factor. The aim of this study was to determine the effects of hemp seed/evening primrose oils (HSO/EPO) supplement on the expression of FOXP3+, STAT3, and interleukin (IL)-17 genes in EAE lymph nodes. EAE was induced by myelin oligodendrocyte glycoprotein peptide in mice, and then the mice were assigned to three treatment groups compared to two control groups (EAE and naive). The histological findings of the spinal cord were evaluated. To determine the expression of FOXP3+, STAT3, and IL-17 genes in the lymphocytes, qRT- PCR was used. Our results showed that EAE severity was reduced in HSO/EPO mice by reducing the expression of STAT3 and IL-17 genes and increasing the expression of FOXP3+ gene, which was confirmed by slight inflammation in the spinal cord. Histological findings showed a significant improvement in the HSO/EPO group. Our findings suggest that the HSO/EPO treatment can be used to ameliorate the demyelination of spinal cord, which was confirmed by immunological and histological findings. Hemp seed/evening primrose oil affects expression of STAT3, IL- 17, and FOXP3 + in experimental autoimmune encephalomyelitis Res Pharm Sci. 2019 Mar 8;14(2):146-154. https://pubmed.ncbi.nlm.nih.gov/31620191/

107. • Atopic dermatitis • Inflammatory disorders • Peripheral neuropathy • Autoimmune conditions • Renal function • Rheumatoid arthritis • Post menopausal symptoms • Reduced cardiovascular risk factors Potential Benefits of Evening Primrose Oil References on following 36 slides of published scientific abstracts

108. Vs. FDA Dietary Supplement Consumers

109. Stock Photo Reenactment of FDA Raid

110. FDA RAIDS AGAINST SUPPLEMENTS MAKERS Raid: Traco Labs, Inc. - November, 1988 Address: 205 S Main St. Seymour, IL 61875 Reason: FDA claimed that black currant oil was an unsafe food additive. Outcome: FDA seized two drums of black currant oil as well as a large quantity of the capsulized product. On Jan. 28, 1993, the U.S. Court of Appeals ruled against FDA. The judge said that FDA's definition of food additive is too broad that even water added to food would be considered a food additive. Raid: Life Extension® - Feb 26, 1987 Address: PO Box 229120, Hollywood, FL 33022 Reason: FDA alleged LEF was selling unapproved drugs (vitamins in U.S.) and drugs from overseas companies. Outcome: FDA seized $500,000 worth of vitamins, computers, files, newsletters, personal belongings. Phones were ripped out of the walls and employees terrorized. The foundation's leaders, Saul Kent and William Faloon, were indicted on 28 criminal counts with maximum prison time of 84 years in November 1991.

111. Raid: Highland Labs - Fall, 1990 Address: Box 199 Mt. Angel, OR 97362 Reason: FDA claimed that product literature was being shipped with products to customers. FDA said this made COQ10 an unapproved drug. Outcome: After spending $250,000 in legal fees, defendant was forced to plead guilty to selling unapproved new drugs. Six months house arrest. $5,000 fine. Raid: Natures Way - June 30, 1992 Address: 1375 N. Mountain Springs Parkway, Springville, Utah 84663 Reason: The FDA seized a quantity of evening primrose oil, both encapsulated and in bulk, from this large manufacturer during a routine inspection. They also seized a truckload of primrose oil on the road. The FDA claimed it was an unapproved food additive. Outcome: Nature's Way filed a lawsuit to get their product back, but was forced to remove the vitamin E from it because the FDA said that Vitamin E has not been approved as a food additive for evening primrose oil. FDA RAIDS AGAINST SUPPLEMENTS MAKERS

112. Raid: Solid Gold Pet Foods - Sept., 1989 Address: 1483 N. Cuyamaca, El Cajon, CA 92020 Reason: FDA had been harassing McGill over labels on her holistic pet food products. In March 1990, an FDA agent seized products from her store without a search warrant and shut down her store. On July 12, 1990, after being indicted, she chose a jury trial. Upon appearing for her trial, she was clapped into leg irons, put into a Maximum Security Federal Prison for 179 days, and fined $10,000. While incarcerated she suffered a near fatal stroke. Outcome: McGill sued the Department of Justice and won a victory on Feb. 20, 1992. She expects to file a $25,000,000 lawsuit against the FDA. Raid: H.A. Lyons mailing Service - Oct. 16, 1990 Address: Driven out of business. Formerly in Phoenix, AZ Reason: Mailing literature on behalf of vitamin companies with no advance warning. Five armed agents backed by an armed policeman raided this home-based business run by a young woman. Outcome: The owner convinced the agents not to seize her checkbook and cash. They did seize all her business records and literature. No charges were filed. FDA RAIDS AGAINST SUPPLEMENTS MAKERS

113. Raid: Nutricology, Inc. - May 9, 1991 Address: 400 Preda Ave. San Leandro, CA 94577 Reason: FDA raided Nutricology, seized their bank accounts and shut them down for 2 days, charging them with wire fraud, mail fraud, selling unapproved drugs, unsafe food additives, and misbranded drugs. Twelve armed agents conducted an exhaustive search of the company's offices and warehouse. Outcome: On May 23, 1991 Federal Judge D. Lowell Jensen denied the FDA's request for a Preliminary Injunction. On Sep. 10, 1991, the FDA appealed to the 9th Circuit Court of Appeals but was again denied. On Sep. 23, 1993, Judge Jensen denied the FDA's motion for summary judgement and granted Nutricology's motion to eliminate the wire and mail fraud charges. Raid: Scientific Botanicals - Fall 1991 Address: 8003 Roosevelt Ave. NE 98115 Phone: (206) 527-5521 Reason: Alleged labeling violations. FDA seized herbal extract products and literature sent to physicians. FDA forced the company to stop using its patented trade names lest they "mislead the consumer." Outcome: FDA slowly released all seized products, forcing the company to comply with all demands under threat of being shut down. Company refuses to talk about their case for fear of reprisal. FDA RAIDS AGAINST SUPPLEMENTS MAKERS

114. Raid: Ye Seekers - June 1992 Address: 1221 Blalock, Houston, TX 77055 Reason: In Feb. 1992, Texas health authorities acting under the direction of the FDA seized 50 products from several health food stores in Texas including Ye Seekers. In June 1992, they seized more than 250 products including aloe vera, zinc, flax seed oil, herb teas, vitamin C and coenzyme Q-10. Outcome: Although more than 410 products were seized, the stores haven't filed suit for fear of reprisals. Raid: Kirwin Whitnah - May 12, 1993 Address: Driven out of business. Formerly in Middletown, CA Reason: Whitnah was promoting the sale of deprenyl. The FDA considered this "selling an unapproved drug." His house raided at gun point when he wasn't home, terrorizing a woman staying at the house. They found no deprenyl. They seized his computer, business records, mailing list, literature, and $4,500 in money orders. Outcome: No charges were filed, but Whitnah was driven out of business. FDA RAIDS AGAINST SUPPLEMENTS MAKERS

115. Raid: International Nutrition Inc - Jun 24 1993 and Aug. 3, 1993 Address: PO Box 1644 Santa Theresa, NM 88008 Reason: FDA seized $1,000,000 worth of vitamin raw materials and products formulated by Dr. Hans Nieper of Germany. Also seized were computers and business records. Outcome: International Nutrition Inc owner agreed to shut down entire business in exchange for no criminal prosecution. Raid: Zerbo's Health Food Store - May 1993 Address: 34164 Plymouth Rd., Livonia, MI 48150 Reason: Alleged distribution by 78-year-old Mr. Zerbo of GH-3 to special customers. Armed U.S. Marshalls and FDA agents cleaned off shelves of coenzyme Q-10, selenium, carnitine, and GH-3. Mr. Zerbo and his daughter Claire, who manages the store, were indicted on charges of "illegal drug trafficking.“ Outcome: Claire Zerbo wanted to fight her indictment, but chose not to do so because the FDA threatened her aging, 78-year-old father who has Parkinson's Disease with 7 years in prison. Because of her fear that her father would die in prison, they both pleaded guilty. Claire will likely receive 3 months probation. Her father is unlikely to go to prison for more than 4 months. FDA RAIDS AGAINST SUPPLEMENTS MAKERS

116. Raid: Thorne Research - Dec. 12, 1991 Address: 901 Triangle Dr. Sand Point, Idaho 83864 Reason: FDA claimed that vitamin products sold by company were "unapproved drugs." FDA agent and three U.S. Marshalls seized the company's entire stock of $20,000 worth of products and 11,000 pieces of literature intended for physicians. Outcome: Thorne initially notified District Court that it would fight but gave up as the expiration date on the seized products was approaching and it became too expensive to continue. Raid: Tahoma Clinic, Dr. Jonathan Wright - May 6, 1992 Address: 24030 132nd Ave. S.E., Kent, WA 98042 Reason: FDA stormed into Wright's clinic with armed sheriffs terrorizing employees and seizing vitamins and other natural therapies, allergy screening equipment, computers, bank records, and medical records. Outcome: In Oct. 1992, Wright filed suit in district court charging unlawful search and seizure and demanded his property back. In response, the FDA convened a Federal Grand Jury and subpoenaed Wright's clinic records. FDA RAIDS AGAINST SUPPLEMENTS MAKERS

117. FDA Advocates that HIV Patients Use Dietary Supplements “There is widespread agreement that nutrition intervention should begin as soon as a diagnosis is made. Once people realize they are HIV positive, they should take steps to improve nutrition… Healthful eating principles, including importance of certain nutrients and use of vitamin and mineral supplements.”

118. April 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382132/ Meta-Analysis Shows Dietary Supplements Slow HIV Progression “…micronutrient supplementation substantially and significantly reduces the risk of HIV disease progression by 38% in adults not on anti-viral therapy.” “adding the mineral selenium improved the outcome significantly” (disease progression reduced by 64%). “addition of zinc to a micronutrient supplement reduced mortality (by 71%)” “The annual cost per patient of micronutrient supplement reported ranged from about $12 to $40/year.”

119. Harsh Penalty for Challenging Government Authority

120. FDA indicted me in November 1991 Sought prison term of >80 Years

121. Dr. Robert Hayling Florida civil rights leader  Jailed for 6 months for asking to be served at a Woolworth's lunch counter.  Offered plea deals in exchange for promise of no future protests.  Released after appeals by Martin Luther King, Jackie Robinson, others http://bigstory.ap.org/article/caec64fd3f9e4731bb9c4bdd801c0879/dr-robert-hayling-florida-civil-rights-leader-dies-86 In 1964 Dr. Hayling imprisoned for defying authority:

122. Lots of Free Publicity Courtesy of FDA Trying to incarcerate Bill Faloon

123. February 4, 1995

124. Life Extension recommended metformin 28 years ago… the FDA went berserk! March 1995

125. 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)

126. Lethal Delays in Approving Ribavirin 1972- Anti-viral effects of ribavirin discovered by ICN Pharma 1983- LifeExtension® recommends ribavirin to its members 1991- FDA brings criminal charges against LifeExtension® founders 1995- FDA brings criminal charges against ICN Pharm founder 1998- FDA approves ribavirin as lifesaving anti-viral therapy Tragic Outcome: 60,000 hepatitis C victims die waiting for ribavirin to be approved. https://www.lifeextension.com/magazine/1998/9/wws

127. Dietary Supplement Health and Education Act of 1994 Sen. Orrin Hatch (R-Utah) Sen. Tom Harkin (D-Iowa) These two Senators Saved Our Supplements: (Prevented FDA from banning/censoring dietary supplements) +

128. FDA Surrenders in 1996 This was the first time the FDA has been forced to give up on a criminal prosecution. https://www.lifeextension.com/magazine/1996/9/freedom By February 1996, Federal Judge Daniel Hurley dismissed all 56 criminal charges against Saul Kent and William Faloon. This victory goes beyond winning in court. The FDA's defeat is a victory for everyone who cherishes freedom in healthcare.

129. FDA Surrenders in 1996 https://www.lifeextension.com/magazine/1996/9/freedom

130. • Forced FDA to allow health claims on dietary supplements. • Forced FDA to accelerate approval of life saving drugs. • Stopped FDA from censoring off-label drug information. Life Extension Victories Against FDA in Courts & Congress

131.  Life Extension was funding 18 research projects aimed at slowing aging in 1987.  On February 26, 1987, FDA raided Life Extension and seized 4,000 copies of newsletter describing the research.  Four years later FDA ordered by a Federal Judge to return seized newsletters, dietary supplements, and pay Life Extension’s attorneys fees.  All anti-aging research torpedoed because of FDA’s actions. FDA Destroys Anti-Aging Research in 1987

133.  England approves metformin:1957  FDA approves metformin: 1994  37-year delay caused millions of American deaths.  66 years later most people don’t know metformin is anti-aging drug. Regulatory Barriers Must be Abolished! Deadly Delays…Urgent Need for Reform

134. 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 pre-diabetic 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:

135. 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.

136. Decades of research reveal demonstrate disease-fighting impact of metformin.

137. 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) Conclusion: “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:

138. 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.

139. Nov 29, 2015

140. April 24, 2016

141. 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

142. Metformin Clinical Trial Announced in 2015. As of ____2023: No known recruiting for metformin anti- aging clinical trial. The study is not listed on ClinicalTrials.gov. The Federal regulations demand that any FDA study conducted within the U.S. must be registered on Clinical Trials.gov prior to commencing-____ 2023.

143. Risk of Delaying Clinical Trials Chronic Diseases May Preclude Systemic Regeneration

144. https://www.science.org/content/article/fda-s-own-documents-reveal-agency-s-lax-slow-and-secretive-oversight-clinical-research FDA Clinical Trial Malfeasance Exposed Oct 1, 2020

145. https://www.science.org/content/article/fda-and-nih-let-clinical-trial-sponsors-keep-results-secret-and-break-law January 13, 2020

146. https://www.bmj.com/content/379/bmj.o2628 “The FDA is “endangering public health” by not being candid about violations that are uncovered during clinical trial site inspections” “The lack of full transparency and data sharing does not allow physicians and other medical scientists to confirm the data independently and make comprehensive risk-benefit assessments…” “The FDA has a long history of failing adequately to oversee clinical trial sites. A report in 2007 by the Department of Health and Human Services’ Office of the Inspector General found the FDA audited less than 1% of the nation’s clinical trial sites between 2000 and 2005 and was highly critical of the agency because it did not have a database of operational clinical trial sites.” BritishMedicalJournalcitesHistoricFDAFailures November 16, 2022 BritishMedicalJournal

147. | Jan. 11, 2023 “FDA Increasingly Halting Human Trials…” Clinical holds by FDA can stifle progress: 2017-2020: 557 clinical holds* 2002-2021: 664 clinical holds 2021-2022: 747 clinical holds “FDA is also saying that's probably part of the reason it's having to press pause on more trials because the technology is just so new.” *average each year

148. Spring/Summer 1985 “Scientists have shown aging process can be safely and effectively “Ironic (FDA) effect…” “This perturbation of the regulatory process will not be corrected until the agencies are relieved of the necessity of making judgments they are not equipped to make.” “The ironic effect is that consumers are denied access to drugs that could benefit them on alleged grounds of public health.” https://www.cato.org/sites/cato.org/files/serials/files/cato-journal/1985/5/cj5n1-10.pdf

149. January 6, 2023 “The reversal of aging could hinge on one huge decision.” “If the FDA classifies aging as a disease, drug companies can take a new approach to curing death.” https://www.popularmechanics.com/science/health/a42419017/anti-aging-drugs-fda-approval/ “Humans Can Start Living Longer —Once the FDA Does This” “Scientists are already targeting proteins in cells to keep them from degenerating.” “TheWHOsupportsthegrowingtrendofcallingagingadisease.”

150. Experimental Human Age Reversal Interventions Urgent Need to Rapidly Accelerate Clinical Trials

152. Support Jonathan Emord for U.S. Senate in 2024! AgainstFDACorruption secure.anedot.com/exploratory-committee-for-jonathan-emord-for-senate/ DONATEAT:

153. Petition FDA-Congress to Amend Clinical Trial Constraints age-reversal.net/FDA

154. Life Extension front-1977 Long Life Magazine - 1978  Life Extension® incorporated in Pompano Beach, Florida in 1977.  Life Extension® did not attract first supporter until 1980.  World’s largest anti-aging group… 500,000 supporters (2023).

155. 1980-1986: Anti-Aging News 1986-1994: Life Extension Report 1994-2023:Life Extension Magazine 43 Consecutive Years of Monthly Publication (> 400,000 copies mailed each month)

156. 1906-2023 = 117 Years of Needless Deaths

157. March 2002 Life Extension Magazine-March 2002

158. Support Jonathan Emord for U.S. Senate in 2024! AgainstFDACorruption secure.anedot.com/exploratory-committee-for-jonathan-emord-for-senate/ DONATEAT:

159. age-reversal.net This presentation and info about aging research available at:

160. Marriott Hotel West Palm Beach, FL What’s Delaying Regenerative Medicine? William Faloon February 9th 2023

161. Regulatory Tyranny: FDA versus Humanity William Faloon Marriott Hotel West Palm Beach, Florida February 9th 2023

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