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Senolytics: A Major Anti-Aging & Wellness Advance

Senolytics: A Major Anti-Aging & Wellness Advance

About Senescent Cells

Senescent cells are cells that have reached a state of permanent cell cycle arrest, meaning they can no longer divide, but they do not die off; instead, they remain alive and can release chemicals that may damage nearby healthy cells, often contributing to the aging process and age-related diseases; essentially, they are "zombie cells" that continue to exist and can have negative effects on surrounding tissues. 

Aging leads to a sharp decline in immune function, precipitating the development of inflammatory conditions.

"As we age we are at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This state of diminished cellular function is driven by cellular senescence"
Reference

With aging, we accumulate too many of these malfunctioning (senescent) cells that refuse to die. Sometimes referred to as “zombie cells,” they pump out toxic compounds that degrade nearby cells and incite chronic inflammation and/or silent inflammation that inflicts systemic damage.1

About Senolitic Activator

Our Senolytic Activator® (for people 45 and older) combines black tea theaflavins, the plant-derived flavonoid apigenin, and ultra-absorbable forms of the bio-flavonoids quercetin and fisetin to help manage senescent cell burden and promote systemic rejuvenation.

Clinical research on dosing protocols is still in its early stages, but current studies suggest that senolytics may not require daily usage

The plant flavonoid fisetin is currently considered one of the most powerful natural senolytics.4,6-20

Enlightened individuals today are taking this highly absorbable fisetin by itself and/or combining it with a once-weekly high potency quercetin + theaflavins for enhanced senolytic effects. 

In youth, cells naturally eliminate themselves if they become damaged or dysfunctional. This process is called apoptosis.

With age, however, we accumulate more senescent cells that emit toxic byproducts, that cause more cells to become senescent. These dysfunctional cells no longer perform basic functions. They instead inflict localized and systemic damage to our healthy cells.

Senescent cells undergo a series of trans-formations that result in their secreting high levels of toxic compounds, collectively referred to as SASP or senescence-associated secretory phenotype.

As a result, the buildup of senescent cells has been shown to accelerate the aging process and increase the risk of age-related diseases, including:23-30
  • Diabetes,
  • Obesity,
  • Stroke,
  • Vision loss,
  • Neurodegenerative disorders,
  • Osteoarthritis,
  • Emphysema, and
  • Cancer.

Research shows that just one senescent cell out of 7,000-15,000 healthy cells can initiate degenerative aging.31

The effects of fisetin go beyond its potent senolytic activity.

Fisetin also:

  • Protects the brain in various models of neurodegenerative disorders,6-8,13-15,20
  • Improves outcomes in people who have suffered strokes,18
  • Helps prevent malignant changes inside cells, 11,12
  • In animal and experimental models, helps fight obesity and type II diabetes tendencies,9,10
  • Reduces the risk of atrial fibrillation after a heart attack, in an animal study,38
  • Reduces levels of pro-inflammatory mediators, in a study of colorectal patients,39 and
  • Based on results of preclinical studies, may inhibit cancer migration and growth and incite cancer cell death.16,40-45

Fisetin also has an ability to impact many of the same cellular pathways that calorie restriction does.2,15, Reducing food intake through a calorie-restricted diet has been shown to slow aging, extend lifespan, and improve resistance to disease.48

What You Also Need To Remember

  • As cells age and accumulate damage, they can enter a state known as cellular senescence. Senescent cells can cause dysfunction and damage throughout the body.

  • Senescent cells are a major driver of aging and the development of many age-related chronic diseases.

  • Recent research has confirmed that cellular senescence also affects the cells of the brain, including neurons.

  • Studies have shown that senescent cells contribute to brain aging and the progression of neurodegenerative disorders like Alzheimer’s disease.

  • Senolytics are compounds that are capable of eliminating senescent cells, rejuvenating tissues and improving their function.

  • In animal models, senolytic therapy reverses the pathology associated with neurodegenerative disease and improves cognitive function.

References

  1. Dodig S, Cepelak I, Pavic I. Hallmarks of senescence and aging. Biochem Med (Zagreb).2019 Oct 15;29(3):030501.
  2. Grynkiewicz G, Demchuk OM. New Perspectives for Fisetin. Front Chem.2019;7:697.
  3. 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.
  4. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. 2018 Oct;36:18-28.
  5. 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.
  6. 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.
  7. 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.2021 Jan 29;18(1):57-71.
  8. 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.
  9. 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.
  10. Jung CH, Kim H, Ahn J, et al. Fisetin regulates obesity by targeting mTORC1 signaling. J Nutr Biochem.2013 Aug;24(8):1547-54.
  11. Khan N, Afaq F, Syed DN, et al. Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. 2008 May;29(5):1049-56.
  12. Li J, Cheng Y, Qu W, et al. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol.2011 Feb;108(2):84-93.
  13. 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.
  14. 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.
  15. Pal HC, Pearlman RL, Afaq F. Fisetin and Its Role in Chronic Diseases. Adv Exp Med Biol.2016;928:213-44.
  16. 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. 2009 Feb;30(2):300-7.
  17. Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond).2015;12(1):60.
  18. 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.
  19. Ying TH, Yang SF, Tsai SJ, et al. Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol.2012 Feb;86(2):263-73.
  20. 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.
  21. A cross over pilot pharmacokinetic study of fisetin 1000mg and formulated fisetin 200mg administered in a single dose to healthy volunteers. Manufacturer’s study (in press for future publication).2020.
  22. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol.2007 Jun;35(4):495-516.
  23. Baker DJ, Petersen RC. Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Invest.2018 Apr 2;128(4):1208-16.
  24. Childs BG, Li H, van Deursen JM. Senescent cells: a therapeutic target for cardiovascular disease. J Clin Invest.2018 Apr 2;128(4):1217-28.
  25. Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest.2013 Mar;123(3):966-72.
  26. Zhu Y, Armstrong JL, Tchkonia T, et al. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care.2014 Jul;17(4):324-8.
  27. Aoshiba K, Nagai A. Senescence hypothesis for the pathogenetic mechanism of chronic obstructive pulmonary disease. Proc Am Thorac Soc.2009 Dec 1;6(7):596-601.
  28. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. 2011 Nov 2;479(7372):232-6.
  29. Yanai H, Fraifeld VE. The role of cellular senescence in aging through the prism of Koch-like criteria. Ageing Res Rev.2018 Jan;41:18-33.
  30. Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun.2017 Sep 4;8(1):422.
  31. Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med.2018 Aug;24(8):1246-56.
  32. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell.2015 Aug;14(4):644-58.
  33. Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. 2017 Jul;21:21-8.
  34. Malavolta M, Bracci M, Santarelli L, et al. Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy. Mediators Inflamm.2018;2018:4159013.
  35. Kirkland JL, Tchkonia T, Zhu Y, et al. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc.2017 Oct;65(10):2297-301.
  36. Jeon OH, Kim C, Laberge RM, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med.2017 Jun;23(6):775-81.
  37. Childs BG, Baker DJ, Wijshake T, et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. 2016 Oct 28;354(6311):472-7.
  38. Liu L, Gan S, Li B, et al. Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction. Int Heart J.2019 Nov 30;60(6):1398-406.
  39. 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.
  40. Bhat TA, Nambiar D, Pal A, et al. Fisetin inhibits various attributes of angiogenesis in vitro and in vivo--implications for angioprevention. 2012 Feb;33(2):385-93.
  41. Li J, Gong X, Jiang R, et al. Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3beta Signal Pathway. Front Pharmacol.2018;9:772.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. Khan N, Syed DN, Ahmad N, et al. Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal.2013 Jul 10;19(2):151-62.
  47. Singh S, Singh AK, Garg G, et al. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. Life Sci.2018 Jan 15;193:171-9.
  48. Anton S, Leeuwenburgh C. Fasting or caloric restriction for healthy aging. Exp Gerontol.2013 Oct;48(10):1003-5.
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