Senolytic Complex

Senolytic Complex is a completely new ‘senolytic’ formulation for fighting the aging process, based on the very latest discoveries in anti-aging medicine.
The term ‘senolytic’, recently coined by the scientific community, describes the ability to eliminate senescent cells (ie, aged cells), the presence of which has been identified in recent years as being, along with oxidative stress and telomere shortening, one of the causes of aging. Since there was previously no way of preventing or slowing down this process, Senolytic Complex constitutes a truly revolutionary treatment.

The formulation contains the most powerful, natural, senolytic compounds identified to date: quercetin (in a form 20 times more bioavailable than standard quercetin), theaflavin, and most importantly, fisetin, an extraordinary flavonoid that’s really setting the scientific community alight.

Who is Senolytic Complex aimed at?

Senolytic Complex is for anyone over 40, whether as a course of treatment, or as long-term supplementation, to eliminate senescent cells and prevent their reappearance.

It is particularly recommended for the following groups of people:

• those who wish to extend their life expectancy;
• those keen to maintain good physical condition and optimal health as they age;
• those who are already suffering from age-related problems (muscle weakness, cardiovascular disorders, vision and hearing impairment, cognitive decline, osteoporosis …) and those who wish to reduce their risk of developing them.

How does Senolytic Complex work?

The discovery of senescent cells invading the body

In 2014, researchers achieved a major advance in the fight against aging. They identified old, worn-out cells in the tissues of subjects aged over 40. Termed ‘senescent’, these zombie-like cells (1) are deformed and unable to divide, and are distributed throughout the body’s tissues. Though no longer functioning normally, they are not eliminated and thus accumulate pathologically.

These cells are rare in young people but increase with age, particularly in adipose tissue, skeletal muscle, blood vessels, the brain, kidneys and skin (2-3).

Their dramatic effects on healthy cells and on the body

Unfortunately, senescent cells do not just take over, they also impede the activity of neighbouring healthy cells by continually releasing pro-inflammatory cytokines (IL-1, IL-6 and IL-8), vesicles and insoluble proteins (fibronectin, collagen) into the extracellular environment (4-7). These substances are really distress calls: they signal to other cells the advanced state of deterioration in which they find themselves, but at the same time, they significantly affect the function of neighbouring healthy cells (8)!

Over the last three years, a number of studies have shown that the level of senescent cells in the body is directly linked to the pace of aging (9) and the development of age-related health problems. Even a small amount of these cells is enough to wreak havoc in tissues(10) and induce the onset of many age-related problems: systemic inflammation, arthritis, atherosclerosis, chronic diseases (11), sarcopenia, cataracts, insulin resistance, vascular hypo-reactivity (12) (13) ...

How can we get rid of these ‘parasitic’ cells?

These cells normally destroy themselves in a process called apoptosis, in order to avoid damaging the body. However, this mechanism does not always work in which case the senescent cells continue to parasitize the body and cause chaos all around them.(14).

Fortunately, researchers have identified several compounds that are specifically capable of repairing this defective mechanism and bringing about the self-destruction of these senescent cells. These extraordinary compounds are called ‘senolytics’.

The first study to identify senolytics was published in 2015 in the well-known scientific journal Aging Cell (15). Quercetin, a natural flavonol compound, combined with an anti-cancer drug, was found to dramatically decrease both the number of senescent cells and secretion of pro-inflammatory factors in the organism studied. In just five weeks, this combination resulted in a significant reduction in mortality and physical deterioration.

Dozens of studies have since identified natural compounds with the same properties (16-17). This has led to the development of a revolutionary new therapy, senolytic treatment, which is able to selectively destroy senescent cells and thus reduce the severity of age-related diseases, increase resilience and longevity, and delay the effects of aging.

The treatment is essentially a massive ‘spring clean’, after which healthy cells regain control of the body and again function at full capacity. It represents a significant advance in the fight against aging.

What is in Senolytic Complex?

Senolytic Complex contains three exceptional senolytic compounds (fisetin, quercetin and theaflavin) and three other anti-aging compounds of interest (vitamin C, nicotinamide mononucleotide and bromelain).

How does Senolytic Complex work?

Fisetin, the most powerful senolytic.

Fisetin is part of the large family of flavonoids, a group of polyphenol antioxidants (18) found in small amounts in strawberries, mangos and certain plants. Of all the flavonoids tested, it was shown to be the most effective at reducing senescent cells (19).

It helps extend longevity (20-21) and reduce markers of senescence in humans. Its hydrophobic nature means it penetrates cells easily via cell membranes (22) and subsequently promotes the self-destruction of abnormal cells (such as senescent cells) by activating various characteristic proteins. One of its specific abilities is to reduce the fraction of senescent cells in the immune system (T lymphocytes and NK cells), thus increasing its beneficial effect, since immune cells are important for clearing out senescent cells (23). In addition, it inhibits the activity of several inflammatory cytokines such as TNFα, IL-6, and the transcription factor NF-Κb, and also offers anti-hyperlipidaemia effects (24).

It is supplied at a dose of 100mg a day (an average 0.4mg a day is consumed from the diet (25)).

For more information on fisetin and its senolytic properties, see: Fisetin is a senotherapeutic that extends health and lifespan.

Quercetin and theaflavin, two other major senolytic compounds

Since senescent cells use different mechanisms to resist programmed cell death (26-27), it’s important that other senolytic compounds are included in the formulation. Quercetin and theaflavin have been selected as two natural senolytics highlighted in the research.

Like fisetin, quercetin is also a member of the flavonoid family. It is extracted from Styphnolobium japonicum, the ‘Japanese pagoda tree’ or ‘honey tree’, and is delivered in a phytosome form which maximises its absorption into the bloodstream. It is recognised as being a benchmark senolytic, in combination with theaflavin, a polyphenol from black tea.

Bromelain, NMN and vitamin C

Senolytic Complex is enhanced by the addition of anti-aging substances that work in symbiosis, such as nicotinamide mononucleotide, an element essential for cellular energy production and longevity of sirtuin proteins, bromelain, an enzyme which actively opposes systemic inflammation, and vitamin C (in its non-acid form), a potent antioxidant that supports the immune system.

How should Senolytic Complex be taken?

Senolytic Complex can either be used as an annual or quarterly treatment (28), or taken continuously, according to your needs. The capsules should be taken at mealtimes.

Senolytic treatment (senotherapy) can be undertaken as a three-step programme:

1. Eliminate senescent cells from your body (even a partial cleansing appears to bring benefits (29)) with the aid of Senolytic Complex.
2. Prevent the development of new senescent cells by improving your lifestyle, protecting yourself against the factors that cause cellular ageing, and strengthening both your DNA repair systems (with the aid of DNA Repair) and antioxidant systems (with the aid ofResveratrol synergy). With its vitamin C and bromelain, Senolytic Complex plays an active role in preventing the reappearance of senescent cells. A number of mechanisms are responsible for their development but two appear to be dominant: high inflammation levels and oxidative stress.
3. Stimulate and boost the immune system so that it too can help clear out senescent cells (with the aid of an immunostimulant mushroom extract).

Attention: fisetin should not be taken in conjunction with antivitamin K drugs, which are commonly-used oral anticoagulants (30).

The very latest research shows that a formulation such as this can produce powerful rejuvenating effects, improve the condition of those affected by age-related health problems, slow down the aging process and extend lifespan.
Exceptional benefits which place this dietary supplement right at the top of anti-aging nutrition and which should come as welcome news for very many people …

Written : Avril 2019

Note: this product should not be used as a substitute for a varied, balanced diet and a healthy lifestyle. It’s important to follow the guidelines on how to take it and the recommended dose, and to use it by the ‘best before’ date. It is not recommended for women who are pregnant or breastfeeding, or for children under 15. Keep out of children’s reach. Store in a cool, dry place

References

1. Swanson E.C., Manning B., Zhang H., Lawrence J.B. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J Cell Biol. 2013;203(6):929–942.
2. Tchkonia T., Morbeck D.E., von Zglinicki T., van Deursen J., Lustgarten J., Scrable H. Fat tissue, aging, and cellular senescence. Aging Cell. 2010;9:667–684
3. Tchkonia T., Morbeck D.E., von Zglinicki T., van Deursen J., Lustgarten J., Scrable H. Fat tissue, aging, and cellular senescence. Aging Cell. 2010;9:667–684.
4. Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5(2):187–95. Epub 2006/04/22. 10.1111/j.1474-9726.2006.00199.x
5. Toutfaire M, Bauwens E, Debacq-Chainiaux F. Biochem Pharmacol. The impact of cellular senescence in skin aging: A notion of mosaic and therapeutic strategies.
6. Oct 15;142:1-12. doi: 10.1016/j.bcp.2017.04.011. Epub 2017 Apr 10.
7. L. Urbanelli, S. Buratta, K. Sagini, B. Tancini, C. Emiliani, Extracellular vesicles as new players in cellular senescence, Int. J. Mol. Sci. 17 (9) (2016).
8. L. Urbanelli, S. Buratta, K. Sagini, B. Tancini, C. Emiliani, Extracellular vesicles as new players in cellular senescence, Int. J. Mol. Sci. 17 (9) (2016).
9. M. Toutfaire et al., The impact of cellular senescence in skin aging: A notion of mosaic and therapeutic strategies, Biochem. Pharmacol. (2017), http://dx.doi.org/10.1016/j.bcp.2017.04.011
10. Campisi J. Aging, cellular senescence, and cancer. Annual review of physiology. 2013;75:685–705. Epub 2012/11/13. 10.1146/annurev-physiol-030212-183653 .
11. Herbig U., Ferreira M., Condel L., Carey D., Sedivy J.M. Cellular senescence in aging primates. Science. 2006;311(5765):1257.
12. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014;17:324–28. doi: 10.1097/MCO.0000000000000065.
13. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife. 2015;4:e12997. doi: 10.7554/eLife.12997.
14. Xu M, Bradley EW, Weivoda MM, Hwang SM, Pirtskhalava T, Decklever T, Curran GL, Ogrodnik M, Jurk D, Johnson KO, Lowe V, Tchkonia T, Westendorf JJ, Kirkland JL. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A Biol Sci Med Sci. doi: 10.1093/gerona/glw154.2016glw154
15. Jeyapalan JC, Sedivy JM. Cellular senescence and organismal aging. Mech Aging Dev. 2008;129(7–8):467–74. Epub 2008/05/27. 10.1016/j.mad.2008.04.001
16. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell. 2015;14(4):644–58. 10.1111/acel.12344
17. Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY). 2016;8(11):2915–26. 10.18632/aging.101100. PMC5191878.
18. Zhu Y, Tchkonia T, Fuhrmann‐Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors. Aging Cell. 2016;15(3):428–35. 10.1111/acel.12445
19. Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal. 2013;19:151–62. doi: 10.1089/ars.2012.4901.
20. MJ Yousefzadeh, Zhu Y et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29.
21. Howitz K.T., Bitterman K.J., Cohen H.Y., Lamming D.W., Lavu S., Wood J.G. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191–196.
22. Wood J.G., Rogina B., Lavu S., Howitz K., Helfand S.L., Tatar M. Sirtuin activators mimic caloric restriction and delay aging in metazoans. Nature. 2004;430(7000):686–689.
23. Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med. 2001;30:433–46. doi: 10.1016/S0891-5849(00)00498-6.
24. Iannello A., Thompson T.W., Ardolino M., Lowe S.W., Raulet D.H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med. 2013;210(10):2057–2069
25. Prasath G.S., Subramanian S.P. Fisetin, a tetra hydroxy flavone recuperates antioxidant status and protects hepatocellular ultrastructure from hyperglycemia mediated oxidative stress in streptozotocin induced experimental diabetes in rats. Food Chem Toxicol. 2013;59:249–255.
26. Arai Y., Watanabe S., Kimira M., Shimoi K., Mochizuki R., Kinae N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr. 2000;130(9):2243–2250
27. Zhu Y., Tchkonia T., Pirtskhalava T., Gower A., Ding H., Giorgadze N. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14:644–658.
28. Niedernhofer L.J., Robbins P.D. Senotherapeutics for healthy aging. Nat Rev Drug Discov. 2018;17(5):377.
29. Kirkland J.L., Tchkonia T., Zhu Y., Niedernhofer L.J., Robbins P.D. The clinical potential of senolytic drugs. J Am Geriatr Soc. 2017;65(10):2297–2301
30. T. Tchkonia, Y. Zhu, J. van Deursen, J. Campisi, J.L. Kirkland, Cellular senescence and the senescent secretory phenotype: therapeutic opportunities, J. Clin. Invest. 123 (3) (2013) 966–972.
31. Touil YS, Auzeil N, Boulinguez F, Saighi H, Regazzetti A, Scherman D, Chabot GG. Fisetin disposition and metabolism in mice: identification of geraldol as an active metabolite. Biochem Pharmacol. 2011;82:1731–39. doi: 10.1016/j.bcp.2011.07.097

1. Swanson E.C., Manning B., Zhang H., Lawrence J.B.Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence.J Cell Biol. 2013;203(6):929-942.
2. Tchkonia T., Morbeck D.E., von Zglinicki T., van Deursen J., Lustgarten J., Scrable H. Fat tissue, aging, and cellular senescence.Aging Cell. 2010;9:667-684
3. Tchkonia T., Morbeck D.E., von Zglinicki T., van Deursen J., Lustgarten J., Scrable H. Fat tissue, aging, and cellular senescence.Aging Cell. 2010;9:667-684.
4. Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al.Senescence-associated beta-galactosidase is lysosomal beta-galactosidase.Aging Cell.2006;5(2):187-95.Epub 2006/04/22. 10.1111/j.1474-9726.2006.00199.x
5. Toutfaire M, Bauwens E, Debacq-Chainiaux F. Biochem Pharmacol.The impact of cellular senescence in skin ageing: A notion of mosaic and therapeutic strategies. Oct 15;142:1-12. doi:10.1016/j.bcp.2017.04.011. Epub 2017 Apr 10.
6. L. Urbanelli, S. Buratta, K. Sagini, B. Tancini, C. Emiliani, Extracellular vesicles as new players in cellular senescence, Int.J. Mol.Sci. 17 (9) (2016).
7. L. Urbanelli, S. Buratta, K. Sagini, B. Tancini, C. Emiliani, Extracellular vesicles as new players in cellular senescence, Int.J. Mol.Sci. 17 (9) (2016).
8. M. Toutfaire et al., The impact of cellular senescence in skin ageing:A notion of mosaic and therapeutic strategies, Biochem.Pharmacol. (2017), http://dx.doi.org/10.1016/j.bcp.2017.04.011
9. Campisi J. Aging, cellular senescence, and cancer.Annual review of physiology.2013;75:685-705.Epub 2012/11/13. 10.1146/annurev-physiol-030212-183653 .
10. Herbig U., Ferreira M., Condel L., Carey D., Sedivy J.M.Cellular senescence in aging primates.Science. 2006;311(5765):1257.
11. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL.Cellular senescence and the senescent secretory phenotype in age-related chronic diseases.Curr Opin Clin Nutr Metab Care.2014;17:324-28. doi: 10.1097/MCO.0000000000000065.
12. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL.Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife.2015;4:e12997. doi: 10.7554/eLife.12997.
13. Xu M, Bradley EW, Weivoda MM, Hwang SM, Pirtskhalava T, Decklever T, Curran GL, Ogrodnik M, Jurk D, Johnson KO, Lowe V, Tchkonia T, Westendorf JJ, Kirkland JL.Transplanted senescent cells induce an osteoarthritis-like condition in mice.J Gerontol A Biol Sci Med Sci. doi: 10.1093/gerona/glw154.2016glw154
14. Jeyapalan JC, Sedivy JM.Cellular senescence and organismal aging.Mech Ageing Dev.2008;129(7-8):467-74.Epub 2008/05/27. 10.1016/j.mad.2008.04.001
15. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al.The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.Aging cell.2015;14(4):644-58. 10.1111/acel.12344
16. Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, et al.Discovery of piperlongumine as a potential novel lead for the development of senolytic agents.Aging (Albany NY).2016;8(11):2915-26.10.18632/aging.101100. PMC5191878.
17. Zhu Y, Tchkonia T, Fuhrmann‐Stroissnigg H, Dai HM, Ling YY, Stout MB, et al.Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors.Aging Cell.2016;15(3):428-35. 10.1111/acel.12445
18. Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: a dietary antioxidant for health promotion.Antioxid Redox Signal.2013;19:151-62. doi: 10.1089/ars.2012.4901.
19. MJ Yousefzadeh, Zhu Y et al.Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine.2018 Oct;36:18-28. doi:10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29.
20. Howitz K.T., Bitterman K.J., Cohen H.Y., Lamming D.W., Lavu S., Wood J.G.Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.Nature. 2003;425(6954):191-196.
21. Wood J.G., Rogina B., Lavu S., Howitz K., Helfand S.L., Tatar M. Sirtuin activators mimic caloric restriction and delay ageing in metazoans.Nature. 2004;430(7000):686-689.
22. Ishige K, Schubert D, Sagara Y.Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms.Free Radic Biol Med. 2001;30:433-46. doi: 10.1016/S0891-5849(00)00498-6.
23. Iannello A., Thompson T.W., Ardolino M., Lowe S.W., Raulet D.H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med. 2013;210(10):2057-2069
24. Prasath G.S., Subramanian S.P.Fisetin, a tetra hydroxy flavone recuperates antioxidant status and protects hepatocellular ultrastructure from hyperglycemia mediated oxidative stress in streptozotocin induced experimental diabetes in rats.Food Chem Toxicol. 2013;59:249-255.
25. Arai Y., Watanabe S., Kimira M., Shimoi K., Mochizuki R., Kinae N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration.J Nutr. 2000;130(9):2243-2250
26. Zhu Y., Tchkonia T., Pirtskhalava T., Gower A., Ding H., Giorgadze N. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell. 2015;14:644-658.
27. Niedernhofer L.J., Robbins P.D.Senotherapeutics for healthy ageing.Nat Rev Drug Discov. 2018;17(5):377.
28. Kirkland J.L., Tchkonia T., Zhu Y., Niedernhofer L.J., Robbins P.D.The clinical potential of senolytic drugs.J Am Geriatr Soc. 2017;65(10):2297-2301
29. T. Tchkonia, Y.Zhu, J. van Deursen, J. Campisi, J.L.Kirkland, Cellular senescence and the senescent secretory phenotype: therapeutic opportunities, J. Clin.Invest. 123 (3) (2013) 966-972.
30. Touil YS, Auzeil N, Boulinguez F, Saighi H, Regazzetti A, Scherman D, Chabot GG.Fisetin disposition and metabolism in mice: identification of geraldol as an active metabolite.Biochem Pharmacol.2011;82:1731-39. doi: 10.1016/j.bcp.2011.07.097