Apigenin: Benefits, Side Effects, and Research
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.
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.
What foods contain apigenin?
Apigenin can be found in many fruits, vegetables and herbs, including parsley, celery, celeriac, red and white sorghum, tarragon, yarrow, basil, rutabagas, oranges, kumquats, onions, wheat sprouts, thyme, spearmint, and cilantro.
While many foods contain apigenin, parsley has plenty of it. Dried parsley typically contains about 45 mg per gram, and dried chamomile flowers contain about 3-5 mg per gram of apigenin. The apigenin content of fresh parsley has been reported to be as high as 215.5 mg per 100 grams. Green celery hearts can contain up to 19.1 mg per 100 grams.
While studies are limited, and the wide range of foods containing apigenin make it hard to estimate an accurate dietary intake, it is likely somewhere in the region of 20 to 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 with at least 2.5 mg of apigenin [1]. The participants had experienced the condition for six months or longer and had a total 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, sleep latency, wake after sleep onset, sleep quality, and number of times that they awakened during sleep.
While it did not appear to have an impact on sleep quality itself, the researchers did observe 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. The trial saw the administration of 1500 mg (500 mg capsules three times daily) of chamomile extract to trial participants [2].
179 participants initially took part in an open-label phase, in which information is not withheld from trial participants and there is no placebo control. In a second, double-blinded phase, 93 participants were randomized to either 26 weeks of continued chamomile treatment or 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 GAD in a randomized, double-blind, placebo-controlled trial. Chamomile extract with a 1.2% apigenin content was administered to trial participants with anxiety and depression, anxiety with a history of depression, or anxiety with no current or past 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. In fact, according to the popular biological aging clock GrimAge, a clock that can accurately predict life expectancy, a person’s GrimAge is accelerated in major depression.
Anti-inflammatory properties
Historically, chamomile tea has been used as a way to reduce inflammation, so it is no surprise that apigenin promotes multiple anti-inflammatory pathways, including p38/MAPK and PI3K/Akt, and that apigenin prevents IKB kinase degradation, which precedes pro-inflammatory NF-κB activation and reduces COX-2 activity [4-6].
Apigenin has been shown to increase the expression of antioxidant enzymes, including GSH-synthase, catalase, and superoxide dismutase (SOD) to combat cellular oxidative and electrophilic stress. White blood cells produce SOD and other reactive oxygen species to kill bacteria. Apigenin boosts the expression of phase II enzyme-encoding genes by blocking the NADPH oxidase complex and its downstream target inflammatory genes via increasing the nuclear translocation of Nrf-2 [7-9].
Apigenin and NAD+
In the context of aging and metabolism, 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.
Animal studies have shown that mice bred to be deficient in CD38 enjoy increased protection from mitochondrial dysfunction and are 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].
Given that CD38 actively degrades both NAD+ and NMN, CD38 inhibitors such as apigenin may be more effective at increasing NAD+ levels rather than boosting them with precursors. In other words, it may be better to treat the cause of NAD+ loss rather than trying to compensate for it. Dr. Nichola Conlon explains more about the intertwined nature of NAD+, CD38, and senescence in her article.
Recent developments
In the last year alone, researchers have discovered new ways of administering and 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 using a method that ensures efficient delivery into the skin. The optimized gel showed significantly better release and penetration of Apigenin into the skin compared to traditional gels [13].
In a study released in February 2023, Dominic Sales and his research team explored the potential of apigenin to enhance the effectiveness of antiretroviral (ART) drugs against HTLV-1 infected cells, a virus associated with a neuroinflammatory autoimmune disease. They discovered that apigenin, by interacting with the aryl hydrocarbon receptor (AhR), can increase the cytotoxicity of ART drugs towards these infected cells, potentially offering a new treatment strategy for patients with HTLV-1-related conditions [14].
In April 2023, Kun Xu and his research team published their 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, a key player in cellular stress response and longevity. This finding suggests Apigenin could be a promising natural treatment option for cardiovascular diseases [15].
In May of 2023, a study by Saima investigated the benefits of apigenin for treating interstitial cystitis, a painful bladder condition. Apigenin was shown to reduce inflammation and oxidative stress in the bladder by suppressing harmful pathways and boosting antioxidant defenses. In addition, apigenin also helped relax bladder muscles, suggesting its potential as a treatment for bladder overactivity and interstitial cystitis [16].
In June of 2022, Abdeen Elkhedir’s research group published a paper on the potential of green pepper’s apigenin flavone glycosides to extend lifespan and enhance stress resistance in the worm C. elegans by activating 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].
Weight was added to this research again in July 2023 when Yu Cheng’s research team also found that chrysin and apigenin can extend lifespan in C. elegans by mildly inhibiting mitochondrial function, a strategy known as mitohormesis. Mitohormesis involves a temporary increase in reactive oxygen species (ROS) that, surprisingly, boosts the worms’ ability to handle oxidative stress and adapt their metabolism, leading to 23% longer lives. This study underscored the importance of certain genes in this lifespan extension, pointing to a promising approach for slowing aging and combating age-related diseases with apigenin [18].
In October 2023, it was discovered that apigenin may be useful in enhancing radiation treatment by undermining DNA repair in cervical cancer cells. Shopnil Akash’s study, published in October 2023, explored the potential of apigenin derivatives in fighting cervical cancer caused by human papillomavirus (HPV) and by targeting DNA polymerase theta, an enzyme that is particularly adept at repairing DNA double-strand breaks. By inhibiting this enzyme, researchers aimed to sensitize cancer cells to DNA-damaging treatments, such as radiation or chemotherapy, thereby enhancing the effectiveness of these treatments. Using computer-based methods, the research identified that certain apigenin compounds could strongly bind to and possibly inhibit HPV proteins and DNA polymerase theta, indicating their 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, particularly in terms of cognitive decline and the risk of dementia. The study showed aged mice given apigenin showed improved memory and learning. Their work also revealed the that these effects were likely driven by apigenin’s influence on genes linked to immune response, inflammation, and neuron function, suggesting it can counteract age-related cognitive decline by modulating these processes. This effect was partly attributed to changes in glial cells, indicating apigenin’s potential in neuroprotection against aging-related changes [20].
Side effects
Apigenin is considered safe when consumed in normal amounts through a diet rich in fruits, vegetables and herbs. However, supplement doses 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 on apigenin, there is currently a lack of aging-related human data beyond cell studies. There is no doubt 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 only a very brief summary, is not intended as an exhaustive guide, and 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 apigenin supplements nor 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.
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[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.
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[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.
