As We See It: Expediting Medical Progress

In 2020, rapid advancements occurred in our understanding of immune function.

But what about those who perish from cancer, diabetes, and dementia?

Why not make heroic attempts to better manage these diseases as well?

I first learned about the havoc that senescent cells inflict on our aging bodies in the 1990s.

Scientists made it clear that for meaningful longevity improvements to happen, the senescent cell burden had to be reduced.

Until recently little could be done.

In 2016, Life Extension^® learned of a flavonoid found in strawberries and apples that demonstrated profound senolytic effects.

The name of the flavonoid is fisetin. The challenge was that fisetin is rapidly metabolized in the digestive tract, leaving little for absorption into the blood.

Many years were spent developing a method to enhance fisetin’s oral bioavailability in order to obtain its systemic benefits.

A low-cost orally absorbable fisetin supplement has finally arrived.

Five clinical trials are now recruiting people to study whether fisetin can combat some of the most difficult health challenges aging humans confront.¹

I sincerely regret delays in moving lifesaving therapies forward. Each day an effective method is postponed means needless loss of life.

This month’s issue reveals validated methods to promote healthy human lifespans.

An article on page 49 of this month’s issue provides fascinating evidence about the disease prevention possibilities of both intermittent fasting and caloric restriction.

The easiest way to accomplish this is to not ingest anything except water, tea, or black coffee for about 16 hours on most days.

I’ve been following this strategy and advocating it for many years. A review article published in the New England Journal of Medicine opened the eyes of even conventional doctors to this health-promoting science.²

Intermittent fasting induces healthy biological responses throughout our aging bodies.

Up until now, most people were challenged to garner these benefits without feeling hungry most of the time.

Obtain Some Fasting Benefits with Fisetin

Consuming fewer calories has long been associated with reduced cancer risks.

Fisetin has been the subject of much scientific interest for its potential to thwart cancer.

Fisetin is a plant flavonoid that selectively removes senescent cells, but research shows it does far more.

The anti-cancer effects of fisetin have been attributed to several properties, including its ability to induce cellular apoptosis and autophagy.^3-12

Apoptosis is the programmed elimination of cells, including those that are older and mutated.

Intermittent fasting or calorie restriction promotes apoptosis and autophagy (removal of waste products inside cells), but so does fisetin.

Anti-Cancer Mechanisms

Instead of undergoing apoptosis, cancer cells override normal processes that remove damaged cells thereby allowing the cancer to proliferate out-of-control.

Fisetin helps restore normal apoptotic processes to help control a wide range of malignant abnormalities.

Autophagy can be described as “cellular housekeeping.”

In healthy cells, autophagy is used to clear out accumulated debris inside of cells. This helps to facilitate normal cell division.

Time-restricted eating and caloric restriction induce these kinds of beneficial changes (apoptosis + autophagy) and may reduce risk of cancers, diabetes, dementia, and a host of metabolic disorders. Fisetin may induce similar benefits.

Curtailing Metastasis

Cells that escape a primary tumor migrate throughout the body and establish metastatic colonies that are often the cause of death in cancer patients.

Fisetin blocks signaling factors that enable cancer cells to spew out protein-degrading enzymes that enable invasiveness and eventual metastasis of tumor cells.^5,13

In a laboratory study using triple negative breast cancer cells, fisetin reduced migration by 76% and inhibited metastasis.¹⁴ The effects were likely due to fisetin interfering with several pathways involved in metastasis.

Impeding Angiogenesis

Malignant cells develop their own blood supply to feed their rapid proliferation.

Angiogenesis refers to the formation of new blood vessels, including into a tumor bed.

Fisetin inhibits angiogenesis by disrupting signals that tumor cells use as a “switch” to promote new blood vessel growth.¹⁵

One lab study found that fisetin inhibited vascular endothelial growth factor (VEGF) growth up to 92% in human umbilical vein endothelial cells.⁴

Mouse studies show fisetin decreases angiogenesis and lung tumor growth.³

Suppressing Inflammation

In preclinical studies, fisetin has been shown to inhibit many inflammatory factors such as TNF-alpha, IL-1 beta, IL-6, and IL-8.^16,17

In a rat model of primary liver cancer, the rats treated with fisetin experienced a normalization of TNF-alphaα and IL-1 beta. These inflammatory cytokines are involved in liver cancer pathology. Fisetin-treated rats had a regression of neoplastic lesions in the liver in this study.¹⁸

In a randomized controlled clinical trial, 37 patients with colorectal cancer undergoing chemotherapy were given either fisetin or placebo for seven weeks. At the end of the trial, plasma levels of IL-8, C-reactive protein, and a protein-degrading enzyme (MMP-7) were significantly reduced in the fisetin group, but not in the placebo group.

The authors suggest that fisetin can improve the inflammatory status in colorectal patients, making it a potential complementary therapy.¹⁹

Further studies are necessary to fully elucidate the usefulness of fisetin as a cancer adjuvant.

Neuroprotection

Fisetin has been studied for its brain-protective properties, which stem partially from its anti-inflammatory effects.

In the context of brain diseases, fisetin has been investigated in Alzheimer’s, Parkinson’s, and Huntington’s, as well as in models of stroke, neurotoxicity and traumatic brain injury.^20,21 Fisetin has displayed promise in many of these areas, and showed some benefit in a clinical trial with stroke patients.²²

As it relates to brain regeneration, fisetin appears to promote neurite outgrowth and brain cell differentiation.²³ In multiple animal studies, fisetin improved learning, memory, and cognition.^24,25

In a mouse model of Alzheimer’s disease, fisetin reduced beta-amyloid deposits and retarded the process by which tau proteins become toxic.²⁶ Fisetin-treated mice in this study had improved memory and diminished neuroinflammation.²⁷

In a mouse model of amyotrophic lateral sclerosis (ALS), mice treated with fisetin had improved survival and redox balance, and reduced motor impairment, compared to control mice.²⁸

In another study, mice with intracerebral-hemorrhage -induced brain injury were treated with fisetin, which lowered multiple indicators of brain trauma and neuroinflammation, including reducing levels of inflammatory cytokines. This suggests the brain injury was diminished.²⁹

Fisetin prevented behavioral and biochemical changes in a rat model of Parkinson’s disease. The treated rats experienced improvements in motor function and dopamine levels, indicating fisetin could have a favorable influence on the pathogenesis of Parkinson’s disease.³⁰

Preventing Stroke Damage in Humans

A clinical trial using fisetin was conducted in 192 patients who had experienced an ischemic stroke. The patients’ onset-to-treatment time had been carefully recorded, as stroke treatment is most effective when administered within three hours of symptom onset.

The patients were treated with the standard of care—an IV injection of the clot-dissolver drug tissue plasminogen activator (tPA)—along with either placebo or 100 mg fisetin in the IV fluid.

After the initial emergency care, patients continued with placebo or fisetin for seven days.

There was no difference in treatment outcome between placebo and fisetin among the patients who were treated between zero and three hours after onset of stroke symptoms.

When onset of symptoms to treatment time was three to five hours, however, there was improvement in the fisetin group compared to the placebo group with the same delayed (three to five hours) treatment time.²²

Interestingly, the patients in the three to five hour delayed treatment group who received fisetin experienced favorable neurological scores almost identical to those who had received standard treatment within three hours.

The researchers concluded that fisetin may be a valuable supplement to clot-dissolving drug treatment for stroke patients, especially in those with delayed treatment after symptom onset.

Diabetic Complications

Diabetic complications such as eye disorders, neuropathy, kidney impairment, and cardiomyopathy may be improved with fisetin administration.

In a mouse model of diabetes, fisetin slowed the advancement of cataracts.³¹ Fisetin also stopped the development of painful neuropathy in diabetic mice.³²

Diabetic rats given fisetin experienced improved body weights and reduced blood glucose and A1c. Fisetin-treated rats had improved lipid profiles and significant lessening of diabetes-induced heart damage.³³

In obese mice fed high-fat diets, fisetin protected kidneys from pathologic alterations and improved kidney function. Fisetin also decreased inflammation in kidneys as demonstrated by reduced levels of TNF-alpha, IL-6, IL-1 beta, and IL-18. ³⁴ These results indicate that fisetin may be beneficial in diabetic kidney disease.

Human Clinical Trials

There are several active clinical (human) trials underway to determine the effects of fisetin,¹ including one in patients with advanced kidney disease, particularly diabetic kidney disease.³⁵

These studies will measure changes in inflammatory markers, stem cell function, kidney function, and more.

Additional clinical trials with diabetic participants that measure glucose levels, insulin resistance, and HbA1c will help determine the role of fisetin in preventing and treating diabetes and its complications.

“Obesity” Control Switch

Fisetin may play a role in regulating obesity by preventing fat-cell production via suppression of mTOR signaling.

When mice were fed a high-fat diet, fisetin attenuated the increase in body weight and white adipose tissue accumulation.³⁶

Other animal studies indicate that fisetin may be helpful in addressing another issue of obesity: fatty liver.^37-40

In one study, mice were given a high-fat diet to induce fatty liver. The fisetin-treated mice had decreased body weight and lipid accumulation in the liver.⁴⁰

What Has Scientists Most Excited?

What got Life Extension® excited about fisetin is its ability to act as a targeted senolytic.

Senolytic compounds selectively remove senescent cells from our aging bodies and have demonstrated remarkable health and longevity improvements.

Currently, the best proven senolytic protocol uses a combination of the cancer drug dasatinib with the flavonoid quercetin.

It is possible that dasatinib could have some off-target effects, such as removing a few healthy cells in the process of purging toxic senescent cells. Dasatinib is nonetheless currently the best documented senolytic agent when combined with quercetin.

With the advent of bioavailable fisetin, it may no longer be necessary to use dasatinib to reduce the senescent cell burden.

In a panel of 10 flavonoids tested in progeroid mice, fisetin was the most potent senolytic.⁴¹

Progeroid mice suffer accelerated aging, just like humans afflicted with progeria. Supplementation with fisetin in progeroid mice resulted in reduced senescent markers in fat, spleen, liver, and kidney.⁴¹

Fisetin has also been shown, in preclinical models, to lower harmful secretions from senescent cells, a phenomenon called the “senescent associated secretory phenotype” (SASPs). This finding of lowered SASP markers indicates that senescent cells were either cleared (meaning fisetin removed senescent cells) or had their senescence reversed.^41-43

In naturally aged mice (roughly equivalent to 75 years in humans), supplementing the diet with fisetin:⁴¹

• Restored tissue homeostasis,
• Reduced age-related pathologies, and
• Extended lifespan.

Similar lifespan-enhancing effects have been seen in other organisms like yeast and flies.^44,45

It has been suggested that such effects may be due to fisetin inhibiting the mTOR pathway and other deleterious factors involved in aging.^44,46-48

Researchers at the Mayo Clinic are conducting clinical trials using very high doses of regular fisetin (not a new bioavailable form) to measure changes in senescent cell burden, inflammation, frailty, and other indicators.⁴⁹

We look forward to findings as more clinical studies about fisetin are published.

What You Might Consider

The senolytic properties of fisetin make it appropriate to use in a modest daily dose of 8 mg in its new bioavailable form, which is equivalent to about 200 mg of regular fisetin.

Fisetin has demonstrated favorable biological effects in preclinical studies, including preventing and suppressing inflammation, regulating cell proliferation, protecting neurons and controlling mTOR.

These benefits are analogous to what happens in response to intermittent fasting—a proactive health and longevity measure that I urge you to consider as a New Year’s resolution.

I eat my last meal around 3 a.m., sleep eight hours and then wake up and immediately begin my 10+ hour workdays. This enables me to not eat anything for 16 or more hours most days.

I augment this intermediate fasting with phytoextracts from green tea and other plants, NAD⁺ boosters, metformin, and now bioavailable fisetin.

At less than 33 cents a day, fisetin is an exciting and affordable new plant extract.

Concept of Daily Senolysis

Young, healthy bodies meticulously remove senescent cells every day.

With age, the senescent cell burden creates a snowball effect of mounting health problems and inability to remove senescent cells until life is no longer sustainable.

Stated in another way, accumulated senescent cells reduce their own removal rate.⁵⁰

With the advent of targeted senolytics like bioavailable fisetin, daily use may be considered, or perhaps weekly as described in the box on the next page.

In This Month’s Issue

Those who follow healthy lifestyles underestimate the degree of bone loss that occurs with normal aging. The article in page 26 describes what Japanese physicians are using to improve bone density and reduce fracture risk.

As the obesity epidemic worsens, more Americans are succumbing to heart attack and other metabolic disorders. The article on page 49 reviews data on how time-restricted eating may lessen the impact of the unhealthy dietary patterns that too many of us engage in.

The article on page 58 describes recent findings on how a plant extract most of you supplement with can improve cardiac function.

Please know that I work around-the-clock to expedite clinical trials aimed at reversing biological aging in older individuals. Your long-standing support enables me to fund a full-time program to transform human research into affordable reality.

For longer life,

William Faloon, Co-Founder
Life Extension Buyers Club

References

1. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=fisetin&cntry=&state=&city=&dist=&Search=Search. Accessed November 19, 2020.
2. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019 Dec 26;381(26):2541-51.
3. Touil YS, Seguin J, Scherman D, et al. Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice. Cancer Chemother Pharmacol. 2011 Aug;68(2):445-55.
4. Bhat TA, Nambiar D, Pal A, et al. Fisetin inhibits various attributes of angiogenesis in vitro and in vivo--implications for angioprevention. Carcinogenesis. 2012 Feb;33(2):385-93.
5. Chien CS, Shen KH, Huang JS, et al. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010 Jan;333(1-2):169-80.
6. Kashyap D, Sharma A, Sak K, et al. Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy. Life Sci. 2018 Feb 1;194:75-87.
7. Kashyap D, Garg VK, Tuli HS, et al. Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Biomolecules. 2019 May 6;9(5):174.
8. Jia S, Xu X, Zhou S, et al. Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways. Cell Death Dis. 2019 Feb 13;10(2):142.
9. Ravichandran N, Suresh G, Ramesh B, et al. Fisetin modulates mitochondrial enzymes and apoptotic signals in benzo(a)pyrene-induced lung cancer. Mol Cell Biochem. 2014 May;390(1-2):225-34.
10. Kang KA, Piao MJ, Madduma Hewage SR, et al. Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway. Tumour Biol. 2016 Jul;37(7):9615-24.
11. Suh Y, Afaq F, Johnson JJ, et al. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 2009 Feb;30(2):300-7.
12. Lim JY, Lee JY, Byun BJ, et al. Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells. Toxicol Rep. 2015 2015/01/01/;2:984-9.
13. Park JH, Jang YJ, Choi YJ, et al. Fisetin inhibits matrix metalloproteinases and reduces tumor cell invasiveness and endothelial cell tube formation. Nutr Cancer. 2013 2013/11/01;65(8):1192-9.
14. Shahi Thakuri P, Gupta M, Singh S, et al. Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling. BMC Cancer. 2020 Jan 2;20(1):4.
15. Syed DN, Afaq F, Maddodi N, et al. Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/beta-catenin signaling and decreased Mitf levels. J Invest Dermatol. 2011 Jun;131(6):1291-9.
16. Wang L, Tu YC, Lian TW, et al. Distinctive antioxidant and antiinflammatory effects of flavonols. J Agric Food Chem. 2006 Dec 27;54(26):9798-804.
17. Park HH, Lee S, Son HY, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct;31(10):1303-11.
18. Maurya BK, Trigun SK. Fisetin Modulates Antioxidant Enzymes and Inflammatory Factors to Inhibit Aflatoxin-B1 Induced Hepatocellular Carcinoma in Rats. Oxid Med Cell Longev. 2016;2016:1972793.
19. Farsad-Naeimi A, Alizadeh M, Esfahani A, et al. Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. Food Funct. 2018 Apr 25;9(4):2025-31.
20. Pal HC, Pearlman RL, Afaq F. Fisetin and Its Role in Chronic Diseases. Adv Exp Med Biol. 2016;928:213-44.
21. Zhang L, Wang H, Zhou Y, et al. Fisetin alleviates oxidative stress after traumatic brain injury via the Nrf2-ARE pathway. Neurochem Int. 2018 Sep;118:304-13.
22. Wang L, Cao D, Wu H, et al. Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial. Clin Appl Thromb Hemost. 2019 Jan-Dec;25:1076029619871359.
23. 23. Maher P. A comparison of the neurotrophic activities of the flavonoid fisetin and some of its derivatives. Free Radic Res. 2006 Oct;40(10):1105-11.
24. 24. Maher P, Akaishi T, Abe K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16568-73.
25. 25. Maher P. Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. Genes Nutr. 2009 Dec;4(4):297-307.
26. 26. Alonso AD, Cohen LS, Corbo C, et al. Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability. Front Cell Neurosci. 2018;12:338.
27. 27. Ahmad A, Ali T, Park HY, et al. Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice. Mol Neurobiol. 2017 Apr;54(3):2269-85.
28. 28. Wang TH, Wang SY, Wang XD, et al. Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK. Neuroscience. 2018 May 21;379:152-66.
29. 29. Chen C, Yao L, Cui J, et al. Fisetin Protects against Intracerebral Hemorrhage-Induced Neuroinflammation in Aged Mice. Cerebrovasc Dis. 2018;45(3-4):154-61.
30. 30. Alikatte K, Palle S, Rajendra Kumar J, et al. Fisetin Improved Rotenone-Induced Behavioral Deficits, Oxidative Changes, and Mitochondrial Dysfunctions in Rat Model of Parkinson’s Disease. J Diet Suppl. 2020 Jan 29:1-15.
31. 31. Kan E, Kilickan E, Ayar A, et al. Effects of two antioxidants; alpha-lipoic acid and fisetin against diabetic cataract in mice. Int Ophthalmol. 2015 Feb;35(1):115-20.
32. 32. Zhao X, Li XL, Liu X, et al. Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors. Pharmacol Res. 2015 Dec;102:286-97.
33. 33. Althunibat OY, Al Hroob AM, Abukhalil MH, et al. Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life Sci. 2019 Mar 15;221:83-92.
34. 34. Ge C, Xu M, Qin Y, et al. Fisetin supplementation prevents high fat diet-induced diabetic nephropathy by repressing insulin resistance and RIP3-regulated inflammation. Food Funct. 2019 May 22;10(5):2970-85.
35. 35. Available at: https://clinicaltrials.gov/ct2/show/NCT03325322?term=fisetin&draw=2&rank=4. Accessed November 19, 2020.
36. 36. Jung CH, Kim H, Ahn J, et al. Fisetin regulates obesity by targeting mTORC1 signaling. J Nutr Biochem. 2013 Aug;24(8):1547-54.
37. 37. Jeon TI, Park JW, Ahn J, et al. Fisetin protects against hepatosteatosis in mice by inhibiting miR-378. Mol Nutr Food Res. 2013 Nov;57(11):1931-7.
38. 38. Gaballah HH, El-Horany HE, Helal DS. Mitigative effects of the bioactive flavonol fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats. J Cell Biochem. 2019 Aug;120(8):12762-74.
39. 39. Cho Y, Chung JH, Do HJ, et al. Effects of fisetin supplementation on hepatic lipogenesis and glucose metabolism in Sprague-Dawley rats fed on a high fat diet. Food Chem. 2013 Aug 15;139(1-4):720-7.
40. 40. Liou CJ, Wei CH, Chen YL, et al. Fisetin Protects Against Hepatic Steatosis Through Regulation of the Sirt1/AMPK and Fatty Acid beta-Oxidation Signaling Pathway in High-Fat Diet-Induced Obese Mice. Cell Physiol Biochem. 2018;49(5):1870-84.
41. 41. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28.
42. 42. Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017 Jul;21:21-8.
43. 43. Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017 Mar 8;9(3):955-63.
44. 44. Grynkiewicz G, Demchuk OM. New Perspectives for Fisetin. Front Chem. 2019;7:697.
45. 45. Pallauf K, Duckstein N, Rimbach G. A literature review of flavonoids and lifespan in model organisms. Proc Nutr Soc. 2017 May;76(2):145-62.
46. 46. Khan N, Afaq F, Khusro FH, et al. Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer. 2012 Apr 1;130(7):1695-705.
47. 47. Kim S, Choi KJ, Cho SJ, et al. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors. Sci Rep. 2016 Apr 26;6:24933.
48. 48. Syed DN, Adhami VM, Khan MI, et al. Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin. Anticancer Agents Med Chem. 2013 Sep;13(7):995-1001.
49. Available at: https://www.mayo.edu/research/clinical-trials/cls-20438802. Accessed November 19, 2020.
50. Karin O, Agrawal A, Porat Z, et al. Senescent cell turnover slows with age providing an explanation for the Gompertz law. Nat Commun. 2019 Dec 2;10(1):5495.