Life Extension Magazine®
Three scientists studying an approach to remove senescent cells

Senolytics: A Major Anti-Aging Advance

Senescent cells emit toxic factors that destroy healthy cells. A multi-pronged approach targets senescent cells so they can be safely removed from the body.

By Michael Downey.

Petri-dish with senescent cells being pipetted in

When old cells become dysfunctional, they’re supposed to die off through a normal process called apoptosis.

But as we age, 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 that inflicts systemic damage.1

Compounds called senolytics remove senescent cells. Preclinical studies show that they can slow or reverse certain aspects of aging.2-5

Nutrients like quercetin and theaflavins (from black tea) have demonstrated senolytic activities and have been widely used in recent years.

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

Its effects are dramatic. Elderly mice given fisetin had their lifespans extended by nearly 10%.4 This may be analogous to a 75-year-old human living about 7.5 years longer.

The challenge up until now was that fisetin is converted into other compounds in the digestive tract. This means very little whole, unaltered fisetin is absorbed into the bloodstream.

Scientists have developed a method to increase fisetin blood levels up to 25 times higher,21 thus enabling fisetin to be distributed throughout the body.

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

Senescent Cells and Aging

A cell going through a natural self-elimination process

In youth, cells naturally eliminate themselves if they become damaged or dysfunctional. This process is called apoptosis.22

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

Removing senescent cells from the body can reduce the cellular drivers of aging and improve overall health.32

That’s where senolytics come in.

Senolytics to the Rescue

Senolytics are compounds that enable the body to remove senescent cells.33,34

They work by reactivating the apoptosis switch in senescent cells. That causes these toxic cells to die and make room for healthy young cells.35

Published scientific studies demonstrate that removing senescent cells from the body improves markers of aging and prolongs lifespan in some models.28,32,33,35,36

In mice with atherosclerosis, removing senescent cells significantly inhibited the growth of arterial plaque and even caused it to regress.37 This could be an important step in preventing heart and blood vessel disease.

In another study, a mouse model of aging showed that removing senescent cells benefited multiple tissues, while delaying the onset and slowing the progression of age-related disorders.28

Fisetin: Today’s Ultimate Senolytic

Scientists have studied many different nutrients, searching for effective senolytics.

Fisetin is the most potent “on target” senolytic known today.4

Fisetin is a flavonoid found in small amounts in strawberries, apples, persimmons, grapes, onions, and other plants. A cell study found that it eliminated about 70% of senescent cells—while doing no harm to healthy human cells.5

These and other effects of fisetin have been shown to increase longevity in various animal models.2,15

Mice given fisetin lived an average of about 2.5 months longer, an almost 10% extension of lifespan—even when treatment started at the human equivalent of 75 years of age.4

Other Benefits of Fisetin

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, 11,12,16,19
  • In animal and experimental models, helps fight obesity and type II diabetes tendencies,9,10,17
  • 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.2,15,46,47 Reducing food intake through a calorie-restricted diet has been shown to slow aging, extend lifespan, and improve resistance to disease.48

What you need to know

Researcher with small vial containing senescent cell sample

Removing Senescent Cells for Better Health

  • With age, we accumulate senescent cells, dysfunctional cells that refuse to die off. These cells are associated with accelerated aging and age-related disease.
  • Senolytics are compounds that can remove senescent cells, helping to maintain optimal function and youthful health. In preclinical studies, senolytics slow or even reverse aging.
  • The compound fisetin is one of the most potent plant-derived senolytics ever discovered. In animal research, it effectively removes senescent cells and boosts longevity. Old mice given fisetin had their lifespans extended by nearly 10%.
  • Quercetin is another plant compound that has significant senolytic effects and improves markers of health. It is even more powerful when enhanced with senolytic black tea compounds called theaflavins.
  • Fisetin, quercetin, theaflavins, and apigenin are nutrients with senolytic activity.

Until recently, there’s been a challenge with oral fisetin: It is rapidly converted into other compounds in the gut. Scientists have solved this problem by combining fisetin with a fiber called galactomannans, isolated from the spice fenugreek.

This formulation has been shown to increase the bioavailability (absorption) of fisetin by as much as 25 times, greatly enhancing its impact.21

The Power of Quercetin

Microscope being used to study quercetin on cells

Before fisetin, quercetin, found in many fruits and vegetables, was one of the first plant-derived flavonoids to be tested as a senolytic.49

Quercetin has long been recognized for a range of benefits, including:

  • Anti-inflammatory activity, shown to protect cells and tissues from injury,50-54
  • Improved markers of aging and extended lifespan in lab studies,55-60 and
  • Reduction or prevention of age-related disease and dysfunction in human studies.61,62

The medical literature supporting the senolytic effects of quercetin has been growing over many years.32,33,35,60,63-65

In a study published in late 2019, quercetin successfully removed senescent cells in the kidneys of mice. This improved function and decreased the fibrosis (scarring) that leads to kidney failure.49

Quercetin can be difficult to absorb.66 Scientists got around this problem by combining it with a type of fatty substance called a phospholipid. The phospholipid serves as a carrier, allowing much more quercetin to enter the bloodstream and exert its effects throughout the body.67

Intermittent or Continual Therapy: Which Senolytic Program is Most Effective?

There’s a great deal of debate in the longevity community about the ideal treatment regimen for senolytic therapies.

For now, intermittent therapy appears to be the best approach to reducing senescent cells.32,33,64 Drugs that reduce expression of pro-inflammatory compounds secreted by senescent cells, for example, seem more effective when taken on an intermittent basis.76

Based upon the available preclinical research, once-weekly ingestion of high doses of fisetin, quercetin, theaflavins, and apigenin appears to be the optimal senolytic approach.

Boosting Quercetin’s Effects

Samples of quercetin being divided up for study

Research has shown that quercetin works even more effectively when coupled with a chemotherapy drug, dasatinib.

When this combination was administered to old mice, its ability to eliminate senescent cells led to improvements in grip strength, coat condition, movement, and overall health.32

The first human study of this combination was published in 2019. Patients with idiopathic pulmonary fibrosis (a progressive lung disease) were given 100 mg/day dasatinib and 1,250 mg/day quercetin on three consecutive days per week for three weeks.68

This improved several measurements of physical activity, including distance walked and walking speed.

Scientists set out to identify a compound that would enhance quercetin’s senolytic effects by the same mechanisms as dasatinib, but without the side effects of a cancer drug.69-72

The most effective candidate they found was a group of compounds in black tea called theaflavins.

In a similar way to dasatinib, theaflavins block an anti-apoptotic protein called BCL-2.69,73 If you wonder what BCL stands for, it is “B-cell lymphoma.”

A compound that blocks BCL-2 might reduce risk of this common malignancy.

In a mouse study, theaflavins demonstrated significant senolytic effects.73

Targeting Toxic Secretions Emitted by Senescent Cells

Apigenin is a flavonoid found in certain herbs, fruits, and vegetables.

In two recent studies, apigenin was found to inhibit the SASP, also known as the senescence-associated secretory phenotype. This resulted in a reduction of pro-inflammatory compounds produced by senescent cells.74,75

Reducing inflammation caused by the SASP while diminishing the senescent cell burden gives a two-pronged strategy for fighting this enemy of longevity.

Quercetin and theaflavins (from black tea) function via separate and complementary mechanisms to purge the body of senescent cells.

Fisetin, a strawberry flavonoid, has been shown to be the most effective senolytic when compared to a panel of flavonoids, removing aged, dysfunctional senescent cells in preclinical studies.

A multi-targeted approach utilizing highly absorbable quercetin and fisetin, plus theaflavins, and apigenin, can attack cellular senescence from multiple angles, helping to rid the body of the damage it causes.

Summary

Group of researchers standing in lab

Old or dysfunctional cells promote chronic inflammation and contribute to loss of function and increased risk for age-related disease.

Senolytics can cleanse the body of these cells, improving organ function and preventing disease.

A plant extract called fisetin has been identified as the most powerful senolytic known so far. An innovative formulation has enhanced fisetin’s absorption up to 25 times.

Fisetin by itself or combined with other known senolytic ingredients such as quercetin and theaflavins, may provide superior senolytic benefits.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

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. EBioMedicine. 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. Carcinogenesis. 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. Carcinogenesis. 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. Akay. 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. Nature. 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. EBioMedicine. 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. Science. 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. Carcinogenesis. 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.
  49. Kim SR, Jiang K, Ogrodnik M, et al. Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin. Transl Res. 2019 Nov;213:112-23.
  50. Saw CL, Guo Y, Yang AY, et al. The berry constituents quercetin, kaempferol, and pterostilbene synergistically attenuate reactive oxygen species: involvement of the Nrf2-ARE signaling pathway. Food Chem Toxicol. 2014 Oct;72:303-11.
  51. Russo M, Spagnuolo C, Tedesco I, et al. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol. 2012 Jan 1;83(1):6-15.
  52. Chen S, Jiang H, Wu X, et al. Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes. Mediators Inflamm. 2016;2016:9340637.
  53. Tanigawa S, Fujii M, Hou DX. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med. 2007 Jun 1;42(11):1690-703.
  54. Yao P, Nussler A, Liu L, et al. Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol. 2007 Aug;47(2):253-61.
  55. Abharzanjani F, Afshar M, Hemmati M, et al. Short-term High Dose of Quercetin and Resveratrol Alters Aging Markers in Human Kidney Cells. Int J Prev Med. 2017;8:64.
  56. Alugoju P, Janardhanshetty SS, Subaramanian S, et al. Quercetin Protects Yeast Saccharomyces cerevisiae pep4 Mutant from Oxidative and Apoptotic Stress and Extends Chronological Lifespan. Curr Microbiol. 2018 May;75(5):519-30.
  57. Duenas M, Surco-Laos F, Gonzalez-Manzano S, et al. Deglycosylation is a key step in biotransformation and lifespan effects of quercetin-3-O-glucoside in Caenorhabditis elegans. Pharmacol Res. 2013 Oct;76:41-8.
  58. Pietsch K, Saul N, Menzel R, et al. Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology. 2009 Oct;10(5):565-78.
  59. Surco-Laos F, Cabello J, Gomez-Orte E, et al. Effects of O-methylated metabolites of quercetin on oxidative stress, thermotolerance, lifespan and bioavailability on Caenorhabditis elegans. Food Funct. 2011 Aug;2(8):445-56.
  60. Chondrogianni N, Kapeta S, Chinou I, et al. Anti-ageing and rejuvenating effects of quercetin. Exp Gerontol. 2010 Oct;45(10):763-71.
  61. Chekalina NI, Shut SV, Trybrat TA, et al. Effect of quercetin on parameters of central hemodynamics and myocardial ischemia in patients with stable coronary heart disease. Wiad Lek. 2017;70(4):707-11.
  62. Javadi F, Ahmadzadeh A, Eghtesadi S, et al. The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women with Rheumatoid Arthritis: A Double-Blind, Randomized Controlled Trial. J Am Coll Nutr. 2017 Jan;36(1):9-15.
  63. Malavolta M, Pierpaoli E, Giacconi R, et al. Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals. Curr Drug Targets. 2016;17(4):447-59.
  64. Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016 Oct;15(5):973-7.
  65. Cherniack EP. The potential influence of plant polyphenols on the aging process. Forsch Komplementmed. 2010;17(4):181-7.
  66. Rich GT, Buchweitz M, Winterbone MS, et al. Towards an Understanding of the Low Bioavailability of Quercetin: A Study of Its Interaction with Intestinal Lipids. Nutrients. 2017 Feb 5;9(2).
  67. Supplier Internal Study. A randomized and crossover pharmacokinetic study of Quercetin 500mg., Quercetin Phytosome 500 mg. and Quercetin Phytosome 250 mg. administered in a single dose to healthy volunteers under fasting conditions. Data on File. 2017.
  68. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-63.
  69. Noberini R, Koolpe M, Lamberto I, et al. Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res. 2012 Oct;66(4):363-73.
  70. Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol. 2012 Feb;23(1):51-7.
  71. Ting PY, Damoiseaux R, Titz B, et al. Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1. PLoS One. 2015;10(3):e0121833.
  72. Leone M, Zhai D, Sareth S, et al. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res. 2003 Dec 1;63(23):8118-21
  73. Han X, Zhang J, Xue X, et al. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med. 2017 Dec;113:59-70.
  74. Lim H, Park H, Kim HP. Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem Pharmacol. 2015 Aug 15;96(4):337-48.
  75. Perrott KM, Wiley CD, Desprez PY, et al. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience. 2017 Apr;39(2):161-73.
  76. Laberge RM, Sun Y, Orjalo AV, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015 Aug;17(8):1049-61.