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Scientist studying plant-based apigenin for removing senescent cells

Suppress Toxic Senescent Cell Secretions

Senescent cell accumulation is a contributor to systemic aging. Natural plant extracts can help reduce the senescent cell burden and lower the harmful compounds they emit.

Scientifically reviewed by: Dr. Gary Gonzalez, MD, in October 2024. Written by: Jason Fitzgerald.

When aged cells lose healthy functionality they’re supposed to die off and their remnants expunged from the body.

Senescent cells do not follow this rule.

They instead linger in a highly activated (toxic) state that damages healthy cells.

Cellular senescence is a major contributor to degenerative disorders and systemic aging.^1-8

Senescent cells can be partially removed from the body using compounds known as senolytics.

Researchers have made another advance in senolytic strategy. They’ve identified that apigenin (a plant extract) reduces harmful compounds that senescent cells emit.

Senolytics Remove Senescent Cells

A few years ago, researchers at the Mayo Clinic showed that it was possible to selectively remove senescent cells using drugs and other compounds known as senolytics.⁹

Initial studies relied on synthetic anti-cancer drugs as part of the senolytic regimen. Navitoclax and dasatinib are two cancer drugs that have been successfully used to eliminate senescent cells.^10,11

One of the most studied senolytic treatments combines dasatinib with a nutrient found in many fruits and vegetables called quercetin. Each compound targets senescent cells in different ways.

In cell culture and animal studies, senolytics remove senescent cells and reduce disease, leading to longer lives for the animals.^8,9,12-14

Last year a study confirmed that senolytics can eliminate senescent cells in human subjects!¹⁵

In this trial, a daily dose of 100 mg of dasatinib and 1,000 mg of quercetin for three days resulted in a significant reduction in senescent cells.

The results were seen in fat tissue, opening the door to potential senolytic treatments for those suffering from obesity, metabolic disease, and more.

What you need to know

A New Senolytic Triple Therapy

As cells age, some of them become senescent. This means they are dysfunctional, but don’t die off like most damaged cells.
Senescent cells rob their tissues of function. They also secrete compounds that incite chronic inflammation, causing damage and dysfunction to surrounding tissues.
Cellular senescence is linked to rapid aging and increased risk for chronic disease.
Senolytics are compounds capable of removing senescent cells. The most common senolytic therapy studied so far is a combination of the plant nutrient quercetin and a cancer drug, dasatinib.
Recent research has found that theaflavins from black tea provide similar senolytic effects as dasatinib.
A third nutrient, called apigenin, provides further protection. It suppresses the secretion of pro-inflammatory compounds by existing senescent cells.
Together, these three plant-based nutrients provide powerful protection against the damage done by cellular senescence.

Plant-Based Senolytics

Using cancer drugs even in very low doses concerns many natural-health enthusiasts.

Scientists have been searching for senolytic agents that do not rely on these drugs. They’ve recently made discoveries showing functional efficacy of plant-based senolytics.

In late 2019, a study was published indicating that the nutrient quercetin is successful as a senolytic agenton its own, without combining it with the cancer drug dasatinib.¹⁶

In this study, quercetin removed senescent cells in the kidneys of mice. This led to improved function and a decrease in the fibrosis (scarring) that causes deterioration and kidney failure.

Quercetin has also been shown to inhibit the proteins that block apoptosis, or programmed cell death, in senescent cells. This makes it easier for other senolytic compounds to eliminate damaged cells from tissues.¹⁷

The data still show that combining quercetin with dasatinib works better than quercetin alone. This led to a search for a plant-based compound that acts like dasatinib, without the side effects.

Scientists have discovered that theaflavins from black tea may act as a senolytic agent by inhibiting cellular receptors Eph, BRC-ABL, and BLC-2^18-21 to clear senescent cells from the body.

Increased activity by a signaling protein called ephrin has been linked to senescence, and dasatinib works in part by stopping ephrin (Eph) receptors from activating.⁹

Theaflavins block ephrin receptor activation and can prevent cell senescence.^18,22

Research shows that theaflavins also inhibit BCL-2 proteins that make it easier to induce death in senescent cells. ²¹

Toxic Secretions Emitted by Senescent Cells

Researchers realized that it’s not enough just to remove senescent cells from the body.

When cells become senescent, they don’t just sit there, as if inert. They undergo a series of transformations that result in their secreting high levels of toxic compounds collectively referred to as SASP or senescence-associated secretory phenotype.

SASP consists of protein-degrading enzymes that damage and destroy surrounding healthy cells and initiate chronic inflammation.²³

This low-level inflammation silently damages tissues and organs, leading to disease, dysfunction, and accelerated aging.²⁴

Persistent inflammation also contributes to weight gain and obesity, which increases risk for type II diabetes and metabolic syndrome, along with cardiovascular disease, cancer, and dementia.^1-4,8,23-28

Los Angeles Times Reports on Senolytics

“This drug cocktail reduced signs of age-related diseases and extended life in mice and human cells”

“…A group led by ... anti-aging researcher James Kirkland not only offers a clear look at the power of senescent cells to drive the aging process, but also a pharmaceutical cocktail that, in mice at least, can slow and even reverse it…”

“Compared with mice that aged normally, those that started the dasatinib-quercetin cocktail at an age equivalent to 75 to 90 years in humans ended up living roughly 36% longer, and with better physical function …”

“Aging…is beginning to look more and more like a disease— and a treatable one at that.” — L.A. Times, July 10, 2018.

Why Senescent Cell Removal is not Enough

It is not yet possible to remove all senescent cells that accumulate in our aging bodies. The best we can do is reduce what’s known as the “senescent cell burden.”

Remaining senescent cells continue secreting SASP that slowly destroys healthy surrounding tissues by degrading proteins and igniting inflammatory fires.

To put this into perspective, scientists calculated that if only one in 7,000 to 15,000 cells is senescent, then age-related problems in physical function started to appear in mice.

To protect against the senescent cell burden, more needs to be done to reduce the emission of toxic SASP.

A Triple-Action Senolytic Approach

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

In two recent studies, apigenin was found to inhibit the SASP. This resulted in a reduction in pro-inflammatory compounds produced by senescent cells.^29,30

Reducing inflammation caused by SASP while diminishing the senescent cell burden is crucial for healthy longevity.

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

A strawberry flavonoid called fisetin may become one of the most effective senolytics, but it is not yet bioavailable enough to induce a systemic benefit.

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

Enhancing Quercetin’s Effects

A challenge to fully benefiting from quercetin is that it can have low oral bioavailability.³¹

To improve quercetin’s absorbability so that the body can obtain higher benefits at lower doses, researchers integrated quercetin into a phytosome.

Phytosomes combine a natural compound (like quercetin) with a plant-based phospholipid carrier.³² This enables much more quercetin to enter the bloodstream to exert its beneficial effects throughout the body.

Summary

Cellular senescence is a major contributor to rapid aging and risk for degenerative illnesses.

Senolytic therapies remove senescent cells from the body, rejuvenating tissues and preventing the chronic damage that senescent cells do.

Major advances have been made in senolytic treatments in the last few years, including demonstrating that these interventions can remove senescent cells in human subjects.

Some of the earliest senolytic compounds used were chemotherapy drugs. Recent research has shown that plant-derived nutrients function via similar senolytic mechanisms.

Quercetin + theaflavins mimic senescent-cell-removing actions of quercetin and dasatinib (the cancer drug).

Apigenin provides added protection by reducing the emissions (SASPs) from residual senescent cells that ignite inflammatory reactions in our aging bodies.

As we await the development of bioavailable fisetin (a plant flavonoid), combinations of theaflavins, quercetin and apigenin are options for people over age 35-45 to consider.

Healthy younger individuals are unlikely to need senolytics as they have not yet acquired a toxic “senescent cell burden”.

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

Calcinotto A, Kohli J, Zagato E, et al. Cellular Senescence: Aging, Cancer, and Injury. Physiol Rev. 2019 Apr 1;99(2):1047-78.
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.
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018 Jun;28(6):436-53.
Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest. 2018 Apr 2;128(4):1238-46.
Soto-Gamez A, Quax WJ, Demaria M. Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions. J Mol Biol. 2019 Jul 12;431(15):2629-43.
Childs BG, Durik M, Baker DJ, et al. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015 Dec;21(12):1424-35.
Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol. 2019 Jan;21(1):94-101.
Palmer AK, Xu M, Zhu Y, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019 Jun;18(3):e12950.
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.
Anderson R, Lagnado A, Maggiorani D, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019 Mar 1;38(5).
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.
Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017 Jul;21:21-8.
Kirkland JL, Tchkonia T, Zhu Y, et al. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. 2017 Oct;65(10):2297-301.
Zhang P, Kishimoto Y, Grammatikakis I, et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019 May;22(5):719-28.
Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-56.
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.
Primikyri A, Chatziathanasiadou MV, Karali E, et al. Direct binding of Bcl-2 family proteins by quercetin triggers its pro-apoptotic activity. ACS Chem Biol. 2014 Dec 19;9(12):2737-41.
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.
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.
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.
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.
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.
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.
Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014 Jun;69 Suppl 1:S4-9.
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.
Liu Z, Wu KKL, Jiang X, et al. The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders. Clin Sci (Lond). 2020 Jan 31;134(2):315-30.
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.
Leonardi GC, Accardi G, Monastero R, et al. Ageing: from inflammation to cancer. Immun Ageing. 2018;15:1.
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.
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.
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).
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.