Apigenin: Benefits And Side Effects

This active ingredient in chamomile tea has traditionally been used to ease anxiety and reduce stress. There have been multiple scientific studies on this traditional use and several studies related to cellular aging.

What is apigenin?

Apigenin is a very common and widely distributed flavonoid in the plant kingdom. Flavonoids are a class of naturally occurring phytochemicals that are found in plant tissues. 

Plants use flavonoids to protect themselves from pathogens and radiation from the sun. Some of them even serve a role in attracting pollinating insects, such as bees, butterflies, and moths. Flavonoids are also used by plants in metabolic regulation.

It is the non-sugar part of several naturally occurring glycosides, molecules that are connected to sugar molecules. It has been used in folk medicines for centuries as a way to treat anxiety and inflammation. Structurally, it is a solid crystalline with a yellow color, and it has been historically used to dye wool.

Apigenin can be found in chamomile, which is normally drunk as a tea. It is obtained from the dried flowers of Matricaria chamomilla, an annual herb native to Western Asia and Europe. The plant has also been naturalized and grows wild in Australia and the United States.

What foods contain apigenin?

Apigenin can be found in many fruits, vegetables and herbs. The chart below shows the typical amounts that are present in some foods.

*The amount of apigenin in chamomile teas varies, with some containing significantly more chamomile than others. Teas prepared from chamomile generally have between 0.8% to 1.2% apigenin content. 

Apigenin is also present in some red wines and beers. But of course, drinking alcohol is not a healthy way to get apigenin into your diet.

The limited number of studies makes it hard to estimate an accurate dietary intake. But it is likely somewhere in the region of 20-25 mg per day. Of course, this could be higher, especially among people whose diets are mostly or completely plant-based.

Of course, like most flavonoids, apigenin is readily available as a dietary supplement. Typical doses start at around 50 mg, though higher doses are also offered.

Insomnia

Chamomile tea has traditionally been used for relieving insomnia for many years. Its usage was so commonplace that researchers have studied its active molecules, which include apigenin. 

A small study saw 34 chronically insomniac adults between 18 and 65 years old given chamomile flower extract. The extract contained at least 2.5 mg of apigenin [1]. The participants had insomnia for six months or longer with a daily sleep time of 6.5 hours or less.

The researchers found that there were no significant differences between the treatment and control groups. These included differences in total sleep time, sleep efficiency, and how long it took to fall asleep. They also included sleep quality and how often people woke up during the night.

While it did not impact sleep quality itself, the researchers observed a modest improvement in daytime functioning. They concluded that chamomile may be useful to improve daytime functioning for people suffering from insomnia.

Anxiety and depression

Chamomile has also been traditionally used for treating anxiety and depression. A randomized, long-term clinical trial for the treatment of generalized anxiety disorder (GAD), was initiated in 2016. Participants were given 1500 mg (500 mg capsules three times daily) of chamomile extract [2].

179 participants initially took part in an open-label phase. This is where information is not withheld from trial participants and there is no placebo control. In a second phase, 93 participants were randomly assigned to two groups. One group received chamomile treatment for 26 weeks, the other received a placebo.

Participants taking chamomile extract were shown to have significantly lower anxiety than participants in the placebo group. The chamomile group also showed a reduction of body weight and mean arterial blood pressure. Chamomile appeared to be safe and had a significant effect on GAD symptoms.

A 2012 study saw chamomile extract used for the treatment of generalized anxiety disorder. The study was a randomized, double-blind, placebo-controlled trial. Chamomile extract with a 1.2% apigenin content was given to participants. Participants had anxiety and depression, anxiety with a history of depression, or anxiety without any depression [3].

The 57 participants were given either chamomile extract or a placebo. The results showed a significant reduction in total Hamilton Depression Rating Scale scores with chamomile treatment. This suggests that chamomile extract may have an antidepressant effect.

This is good news, as research shows that depression can have a negative impact on the rate at which we age. According to the biological aging clock GrimAge, a clock that can accurately predict life expectancy, major depression accelerates aging.

Anti-inflammatory properties

Chamomile tea has a long history of reducing inflammation. It is not surprising that it promotes anti-inflammatory pathways, like p38/MAPK and PI3K/Akt. It also stops IKB kinase from breaking down. This breakdown happens before pro-inflammatory NF-κB is activated and reduces COX-2 activity [4-6].

Apigenin can increase the levels of antioxidant enzymes. These include GSH-synthetase, catalase, and superoxide dismutase (SOD). This helps fight oxidative and electrophilic stress in cells. White blood cells produce SOD and other reactive oxygen species to kill bacteria. 

Apigenin increases the expression of phase II enzyme genes. It does this by blocking the NADPH oxidase complex and the downstream inflammatory genes it targets. This is facilitated by increasing the nuclear translocation of Nrf-2 [7-9].

Apigenin and NAD+

Apigenin and quercetin have both been found to inhibit the activity of CD38 [10-11]. CD38 is an enzyme that consumes nicotinamide adenine dinucleotide (NAD+) in ever-increasing amounts as we get older. NAD+ is a coenzyme found in all living cells and is essential for cellular function, DNA repair, and life.

Studies show that mice bred to be deficient in CD38 enjoy increased protection from mitochondrial dysfunction. They are also resistant to diabetes as they age. This protective action is regulated via the mitochondrial sirtuin SIRT3. Mice treated with apigenin show an increased level of NAD+ and are resistant to the effects of high-fat diets [12].

CD38 breaks down both NAD+ and the NAD+ precursor Nicotinamide mononucleotide (NMN). This means that CD38 inhibitors like apigenin might work better to raise NAD+ levels than using precursors. In other words, it may be better to treat the cause of NAD+ loss rather than trying to compensate for it. 

Recent developments

In recent years, researchers have discovered new ways of applying apigenin to the landscape of human health and longevity.

The development of a better topical delivery for apigenin came in January 2023. Mohammad Adnan’s research focused on creating a skin-applied gel containing apigenin. The optimized gel showed significantly better release and penetration of Apigenin into the skin compared to traditional gels [13].

February 2023, Dominic Sales explored the potential of apigenin to enhance the effectiveness of antiretroviral (ART) drugs. The focus of the study was HTLV-1 infected cells. This is a virus associated with a neuroinflammatory autoimmune disease [14]. 

They found that apigenin interacts with the aryl hydrocarbon receptor (AhR) to increase the cytotoxicity of ART drugs. This potentially offers a new treatment strategy for patients with HTLV-1-related conditions.

In April 2023, Kun Xu published his findings on how Apigenin protects against heart damage caused by oxidative stress. They demonstrated that Apigenin significantly reduces damage and improves heart cell health by activating the SIRT1 signaling pathway. SIRT1 is a key player in the cellular stress response and longevity. This finding suggests Apigenin might be a promising natural treatment option for cardiovascular diseases [15].

In May 2023, a study by Saima investigated the benefits of apigenin for treating interstitial cystitis. It reduced oxidative stress and inflammation by suppressing harmful pathways and boosting antioxidant defenses in the bladder. Apigenin also helped relax bladder muscles, suggesting its potential as a treatment for bladder overactivity and interstitial cystitis [16].

In June 2022, Abdeen Elkhedir published a paper exploring how apigenin flavone glycosides in green peppers might extend lifespan. The paper also looked at how these compounds can improve stress resistance. 

They showed in C. elegans it activated a cluster of anti-aging genes, including daf-2, daf-16, sod-3, hsp-16.2, skn-1, gst-4, gcs-1, jnk-1, and sir-2.1, along with stress response mechanisms [17].

In July 2023, Yu Cheng’s research team built on earlier studies. They found that chrysin and apigenin can extend lifespan in C. elegans by mildly inhibiting mitochondrial function. This is known as mitohormesis. 

Mitohormesis involves a temporary increase in reactive oxygen species (ROS) that boosts the worms’ ability to handle oxidative stress and adapt their metabolism. This led to a 23% longer lifespan in the study. 

This study underscored the importance of certain genes in lifespan extension. It is a promising approach for slowing aging and combating age-related diseases with apigenin [18].

In October 2023, Shopnil Akash’s team looked into how apigenin derivatives may help fight cervical cancer. They focused on cancer caused by the human papillomavirus (HPV). 

Apigenin derivatives target and inhibit DNA polymerase theta in these cancerous cells. This enzyme allows the repair of DNA double-strand breaks in cancer cells. By inhibiting this enzyme, researchers aimed to sensitize cancer cells to DNA-damaging treatments, such as radiation or chemotherapy. This could potentially enhance the effectiveness of these treatments. 

Using computer-based methods, the research identified that certain apigenin compounds can inhibit HPV proteins and DNA polymerase theta. This suggests their potential effectiveness in cancer treatment. These findings are supported by various computational tests, suggesting the need for further studies [19].

In February 2024, Alyssa Cavalier and associates explored how apigenin affects aging brains. In particular in the context of cognitive decline and the risk of dementia. The study showed aged mice given apigenin showed improved memory and learning [20].

Their work also suggests this was likely driven by apigenin’s influence on immune response, inflammation, and neuron function. This suggests it may counteract age-related cognitive decline by modulating these processes. The effect was partly attributed to changes in glial cells. This indicates apigenin’s potential in neuroprotection against aging-related changes.

Side effects

Apigenin is considered safe when consumed in normal amounts through a diet rich in fruits, vegetables and herbs. However, supplements tend to deliver a significantly higher amount of apigenin than would be generally consumed via dietary means. 

Higher doses of apigenin can cause stomach discomfort, and people should cease using it immediately and consult medical professionals. Allergic reactions can also occur as a response to chamomile tea or apigenin.

The future of apigenin

Despite there being a number of interesting animal studies with apigenin, there is currently a lack of human data. No doubt there is more to learn about apigenin, including its possible utility as a senolytic or senomorphic. But more research is needed before anyone can make any conclusions regarding the geroprotective effects of apigenin.

Disclaimer

This article is not intended as an exhaustive guide. It is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse any product or supplement vendor, and all discussion here is for scientific interest.

Literature

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[2] Mao, J. J., Xie, S. X., Keefe, J. R., Soeller, I., Li, Q. S., & Amsterdam, J. D. (2016). Long-term chamomile (Matricaria chamomilla L.) treatment for generalized anxiety disorder: A randomized clinical trial. Phytomedicine, 23(14), 1735-1742.

[3] Amsterdam, J. D., Shults, J., Soeller, I., Mao, J. J., Rockwell, K., & Newberg, A. B. (2012). Chamomile (Matricaria recutita) may have antidepressant activity in anxious depressed humans-an exploratory study. Alternative therapies in health and medicine, 18(5), 44.

[4] Lee, J. H., Zhou, H. Y., Cho, S. Y., Kim, Y. S., Lee, Y. S., & Jeong, C. S. (2007). Anti-inflammatory mechanisms of apigenin: inhibition of cyclooxygenase-2 expression, adhesion of monocytes to human umbilical vein endothelial cells, and expression of cellular adhesion molecules. Archives of pharmacal research, 30(10), 1318-1327.

[5] Lapchak, P. A., & Boitano, P. D. (2014). Effect of the pleiotropic drug CNB-001 on tissue plasminogen activator (tPA) protease activity in vitro: Support for combination therapy to treat acute ischemic stroke. Journal of neurology & neurophysiology, 5(4).

[6] Huang, C. H., Kuo, P. L., Hsu, Y. L., Chang, T. T., Tseng, H. I., Chu, Y. T., … & Hung, C. H. (2010). The natural flavonoid apigenin suppresses Th1-and Th2-related chemokine production by human monocyte THP-1 cells through mitogen-activated protein kinase pathways. Journal of medicinal food, 13(2), 391-398.

[7] Huang, C. S., Lii, C. K., Lin, A. H., Yeh, Y. W., Yao, H. T., Li, C. C., Wang, T. S., & Chen, H. W. (2013). Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Archives of toxicology, 87(1), 167–178.

[8] Telange, D. R., Patil, A. T., Pethe, A. M., Fegade, H., Anand, S., & Dave, V. S. (2017). Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 108, 36–49.

[9] Paredes-Gonzalez, X., Fuentes, F., Jeffery, S., Saw, C. L., Shu, L., Su, Z. Y., & Kong, A. N. (2015). Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharmaceutics & drug disposition, 36(7), 440–451.

[10] Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., … & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139.

[11] Schultz, M. B., & Sinclair, D. A. (2016). Why NAD+ declines during aging: It’s destroyed. Cell metabolism, 23(6), 965-966.

[12] Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., … & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084-1093.

[13] Adnan, M.; Afzal, O.; S. A. Altamimi, A.; Alamri, M.A.; Haider, T.; Faheem Haider, M. (2023) Development and Optimization of Transethosomal Gel of Apigenin for Topical Delivery: In-Vitro, Ex-Vivo and Cell Line Assessment. Int J Pharm, 631, 122506.

[14] Sales, D.; Lin, E.; Stoffel, V.; Dickson, S.; Khan, Z.K.; Beld, J.; Jain, P. Apigenin Improves Cytotoxicity of Antiretroviral Drugs against HTLV-1 Infected Cells through the Modulation of AhR Signaling. (2023) Neuroimmune Pharmacology and Therapeutics, 2, 49.

[15] Xu, K.; Yang, Y.; Lan, M.; Wang, J.; Liu, B.; Yan, M.; Wang, H.; Li, W.; Sun, S.; Zhu, K.; et al. Apigenin Alleviates Oxidative Stress-Induced Myocardial Injury by Regulating SIRT1 Signaling Pathway. (2023) Eur J Pharmacol, 944, 175584

[16] Saima; Anjum, I.; Mobashar, A.; Jahan, S.; Najm, S.; Nafidi, H.A.; Bin Jardan, Y.A.; Bourhia, M. (2023) Spasmolytic and Uroprotective Effects of Apigenin by Downregulation of TGF-β and iNOS Pathways and Upregulation of Antioxidant Mechanisms: In Vitro and In Silico Analysis. Pharmaceuticals 2023, Vol. 16, Page 811, 16, 811

[17] Elkhedir, A.E.; Iqbal, A.; Zogona, D.; Mohammed, H.H.; Murtaza, A.; Xu, X. (2022) Apigenin Glycosides from Green Pepper Enhance Longevity and Stress Resistance in Caenorhabditis Elegans. Nutrition Research, 102, 23–34.

[18] Cheng, Y.; Hou, B.H.; Xie, G.L.; Shao, Y.T.; Yang, J.; Xu, C. (2023) Transient Inhibition of Mitochondrial Function by Chrysin and Apigenin Prolong Longevity via Mitohormesis in C. Elegans. Free Radic Biol Med, 203, 24–33

[19] Akash, S.; Bayıl, I.; Hossain, M.S.; Islam, M.R.; Hosen, M.E.; Mekonnen, A.B.; Nafidi, H.A.; Bin Jardan, Y.A.; Bourhia, M.; Bin Emran, T. (2023) Novel Computational and Drug Design Strategies for Inhibition of Human Papillomavirus-Associated Cervical Cancer and DNA Polymerase Theta Receptor by Apigenin Derivatives. Scientific Reports 2023 13:1, 13, 1–22.

[20] Cavalier, A.N.; Clayton, Z.S.; Wahl, D.; Hutton, D.A.; McEntee, C.M.; Seals, D.R.; LaRocca, T.J. (2023) Protective Effects of Apigenin on the Brain Transcriptome with Aging. Mech Ageing Dev, 217, 111889.