You’ve likely heard about resveratrol, a potent antioxidant that has been most profoundly associated with the health benefits of red wine? Well, this next nutrient called pterostilbene (and pronounced ter-oh-stil-been), is chemically similar, and has a similar role in physiology with one significantly important difference…
Pterostilbene mechanisms of action
Resveratrol is actually a precursor molecule of pterostilbene (1), and like resveratrol, pterostilbene is a potent plant polyphenol most abundantly found in blueberries. Research conducted into its effects gives it credit for the potential preventative and therapeutic influence it has on many different diseases, including some of the top life-threatening illnesses of our time, such as heart disease, cancer, diabetes and Alzheimer’s disease.
It’s these effects that have a critical role to play in health, disease and the effects of ageing.
The most important difference to consider when we compare these effects of resveratrol and pterostilbene is that pterostilbene is far more bioavailable.
You see, the chemical structure of resveratrol means it is readily broken down by the liver, which reduces the time it has to take effect. Pterostilbene, on the other hand, has a slightly different chemical structure, which makes it harder for the body to metabolize it so quickly, and thus easier for the molecules to cross through cell membranes – both of which are a good thing when you want the benefits from such a potent health-boosting molecule (2)! In fact, studies have shown that pterostilbene has an 80% bioavailability, while most forms of resveratrol only 20% (3).
But how, in particular, is it beneficial to health- and lifespan?
Considered highly safe for human consumption (4), these are some of the major mechanisms through which pterostilbene is believed to exert its effects (5).
- Mimics a calorie-restricted diet
- Counteracts mitochondrial dysfunction
- Improves metabolic function
- Promotes fat mobilization and breakdown
Research also shows that, like resveratrol, pterostilbene has antioxidant and anti-inflammatory properties, which further promotes its effects on health, the risk of disease and healthy ageing.
While a 2017 study suggests that more research is needed to expand on the benefits of pterostilbene, there are a number of studies that show these effects (6).
Pterostilbene as an anti-cancer agent
Incident rates of breast cancer in women and men are on the increase. Obesity and nutrient-poor diets are said to be two of the major contributing factors (7). While increasing the intake of healthy food and losing weight provide protection from cancer, several studies have shown that those who take blueberry extracts and pterostilbene have a lower risk of breast cancer development. There’s also evidence to support the use of pterostilbene in the treatment of breast cancer, where the compound alters the cellular oxidative activity that is essential for the continuation of proliferation and function of cancer cells.
Tested on human breast cancer cells, research in 2010 shows that treatment with pterostilbene induces cell suicide and inhibited cell proliferation along with exerting potent antioxidant activity against the production of oxide molecules with amplifying the effects of the oxide degrading enzyme superoxide dismutase (SOD) (8).
In fact, it has been shown that pterostilbene may have a 5.7-fold increase in SOD activity. In addition, when combined with quercetin, another potent antioxidant, rats induced to develop cancer showed significant tumor regression9.
One study, conducted on pregnant and breast-feeding rats showed that those who were fed a blueberry-containing diet had an increase in the signalling of pathways involved in tumor suppression as well as a decrease in the number of dividing cells, which presents a lower risk of cancer cell development10. Several other studies have discovered how pterostilbene affects various pathways involved in tumor development. It has been found to act on human growth factor, decreasing its effect on the PI3 K/AkT/NK-κB pathway, which plays a significant role in breast tissue carcinogenesis. Inhibition of HGF also reduced the risk of cell migration and matrix metalloproteinase-2 and -9, which further decreases the risk of development and spread of cancer cells.
The antioxidant activity of pterostilbene also plays an important role in its anti-cancer activities. Research has shown that when pterostilbene is applied to breast cancer cells in a laboratory setting, it causes the energy centers of the cells to self-destruct11. Some of the mechanisms that have been found to produce these effects are through the induction of the caspase-3, Bax and p53 pathways.
Brain health boosting properties of pterostilbene
In the brain, pterostilbene has been shown to have potent protective effects against functional deficits.
Using a mouse model that has been created to study accelerated ageing, inducing Alzheimer’s disease in these animal studies showed that cellular stress and inflammation are two of the most prominent markers of the pathology of the disease. Mice that were treated with low dose pterostilbene for two months fared far better on tests than their untreated counterparts, which showed that pterostilbene is a potent modulator of cognitive ability and a mediator of cellular stress. The effect was independent of the longevity pathway of SIRT1 that resveratrol exerts its effects on12.
Three of the major characteristics of Alzheimer’s disease are the accumulation of amyloid-B plaques in the brain, the appearance of neurofibrillary tangles and neuronal cell death, all of which interfere with the ability to transmit and receive signals across the brain and throughout the body. While an effective treatment for the disease is still being investigated, there are a variety of options that may slow the progression of the degeneration, and even reduce the risk of its development.
When it comes to pterostilbene, we’re interested in how it’s anti-inflammatory actions may affect the brain. One of the most important pathways that has been investigated is the NLRP3/caspase-1 pathway, which regulates the immune response, and has been shown to be involved in the development of AD. New research suggests that inhibition of NLRP3 may be a new therapeutic target for the disease. Pterostilbene was shown to do just that, inhibiting the upstream regulators of NLRP3, which suppresses its effects on the development of neuroinflammation13.
In addition to AD, this effect of pterostilbene on the NLRP3 pathways may prove beneficial in patients that have had a stroke. In a brain haemorrhage model, treatment with pterostilbene reduced the inflammation resulting from the damage. Inflammatory chemicals active caspase-1, IL-1β, and IL-18 are also heightened in stroke patients, which are markedly decreased in pterostilbene treatment groups.
Heart health and vascular protective effect of pterostilbene
One of the deadliest diseases of our time is cardiovascular disease (CVD). Risk factors for its development include cigarette smoking, a sedentary lifestyle and eating a diet low in nutrient-rich fruit and vegetables.
All three of these factors have one thing in common: they cause oxidative stress in the heart and circulatory system. That’s where pterostilbene comes in.
Pterostilbene has been shown in a rat model to have numerous protective effects on cardiovascular health through effects on regulation of vascular smooth muscle and endothelial cell function. Proliferation of vascular smooth muscle cells has been linked to the etiology of athersclerotic disease, where pterostilbene has been shown to inhibit this proliferation8. There is also evidence to suggest the antioxidant protective effect of pterostilbene on endothelial cells, which reduce the oxidation of low-density lipoprotein, a marker of atherosclerosis14.
As a potent antioxidant, it has been shown to improve the risks of CVD by scavenging free radicals and reactive oxygen species, with many studies providing evidence to this effect. In a study using a rat model, researchers fed mice a blueberry-enriched diet for 3 months, which resulted in a 22% reduction in the severity of an induced heart attack when compared to mice who were fed a diet without the blueberry extract15. Within two weeks of the event, the blueberry-fed rats also showed improved recovery rates when compared to the controls.
Pterostilbene offers protective effects against plaque formation within the artery walls, which leads to a condition called atherosclerosis. The compound has been found to regulate smooth muscle cells and endothelial cell function. In the presence of pterostilbene, platelet aggregation is reduced, which decreases the accumulation of plaques16.
Another concern around the formation of artery-occluding plaques is the oxidation of cholesterol. LDL, which is often referred to as bad cholesterol, becomes oxidised by free radicals, which makes it more likely to become sticky and form masses that accumulate in the artery walls. Pterostilbene has been shown to promote autophagy, through activation of the specific energy pathway, called AMPK, boosting intracellular calcium levels and through mTOR signalling. The activation of these pathways counteracts the atherosclerosis-inducing effects that involve the build up of abnormal protein molecules which results from increased oxidation of LDL17.
While clinical studies still need to be conducted to replicate the results of the use in the prevention and treatment of pterostilbene in CVD, there is clinical relevance for its use as a potent antioxidant due to its proven effects on the LOX-1, NF-kB and SOD pathways, all three of which pay a role in the risk of atherosclerosis development. In one small study, it was shown that a diet including 250g of blueberries for three weeks has a significant impact on
Pterostilbene reduces the risks associated with diabetes
With the rise in cases of obesity combined with an increasingly sedentary type of lifestyle, diabetes has become a prevalent disease. Insulin resistance plays an important role in the development of diabetes, and is characterized by imparied insulin regulation and function. While it has been proposed that a change in diet and physical activity are modifications that have a significant and positive benefit on the risk and treatment of the disease, the addition of antioxidants and anti-inflammatory compounds may provide further therapeutic possibilities.
The pathway we’re typically interested in when it comes to glucose metabolism is the PI3K/Akt (phosphoinositide 3-kinase/ protein kinase B) signaling pathway. Pharmaceutical drugs that address the breakdown in the mechanisms involved in insulin and blood sugar management in diabetes, work by y by activating the peroxisome proliferator-activated receptor γ (PPARγ) in muscles cells as well as in the liver and fat cells, which improves the use of glucose by the body’s cells. Research conducted into the use of pterostilbene in metabolic issues such as diabetes, have elucidated its effects on these two pathways.
Using diabetic rats, researchers found that pterostilbene, administered to diabetics rats, had numerous benefits. 50 rats, divided into five groups were given either 20 mg/kg, 40 mg/kg and 80 mg/kg of pterostilbene, 5 mg/kg of a specific diabetes drug and the last group acted as the control.
In the pterostilbene groups, even moderate intake of pterostilbene was shown to have potent antioxidant-boosting effects, rats had significantly lower levels of common inflammatory markers, overall cholesterol and insulin indices improved, and the rats had lower blood sugar levels following an oral glucose tolerance test.
When the above mentioned pathways were investigated, it was found that the diabetic control group showed that they had a suppressive effect on the PPARγ proteins while those diabetic rats treated with pterostilbene had significantly up-regulated expression of these proteins. Additionally, increased activation was noted in the proteins involved in the expression levels of PI3K, p-Akt and GLUT4, which was significantly higher than what was noted in the other group18.
These results need to be replicated in large-scale human trials, however, the positive evidence gathered from animal and tissue studies shows a significant amount of promise for the use of pterostilbene in the prevention and treatment of diabetes alongside dietary and lifestyle changes.
Digestive benefits related to pterostilbene
The number of cases of chronic liver disease is on the rise. In addition to alcoholism, non-alcoholic fatty liver disease (NAFLD), which progresses into non-alcoholic steatohepatitis (NASH) in severe cases, can cause serious liver damage. The most common cause of NAFLD is poor diet, with high intakes of unhealthy fats and refined carbohydrates. As a result, fatty tissue develops within and around the liver cells, reducing the capacity of the liver to function optimally, which induces inflammatory reactions. The inflammation, and resulting tissue damage may then develop into the more serious form of liver disease, NASH.
In addition to the fatty tissue, the cells of the liver begin to proliferate. The increased number of free radicals produced within the liver, causes the tissue to become fibrous, which leads to hardening of areas of the liver, causing structural damage to the organ.
While much of the research has been conducted in animal models, the use of pterostilbene and its powerful antioxidant properties, may play a role in preventing the severity of the disease. When blueberry juice was fed to rats with fibrotic tissue in their livers, it was noted that there was an increase in the enzyme superoxide dismutase (SOD) as well as liver-protective enzymes such as GST. Two markers of severe liver injury, namely hyaluronic acid and ALT were reduced in the blueberry treated rat group19. A previous study20 by the same researchers had found that specific expressions of Nrf-2, Nqo1, and HO-1 were involved in the protective mechanisms of blueberries, which were consistent results found in their latest study.
When using the blueberry extract pterostilbene, research has found the same results. Again using animal models, pterostilbene has been shown to reduce the damaging effect of hydrogen peroxide on the liver cells, specifically reducing the effect H2O2 has on gap junctional intercellular communication (GJIC). GJIC is an important cellular communication pathway. When the signalling is disrupted, as is seen in cellular damage, there is a higher risk for the development of tumors21. The potent antioxidant effect of pterostilbene has thus been shown to suppress the effects of carcinogenic pathways, which makes it a potential agent with therapeutic benefits against liver cancer.
Research in this area has not yet proceeded to large-scale clinical trials, however, when pterostilbene was introduced into a metastatic cell model in the laboratory setting, evidence showed that the compound significantly inhibited vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and MMP, all of which are upregulated in cancer cell development. These findings also showed that there was little toxic effect as a result22.
Colon cancer deaths, according to the American Cancer Society have increased 1% year on year between 2007 and 2016. It has been suggested that pterostilbene offers a natural approach to colon cancer, where treatment in rats has shown that the compound downregulates the inflammatory enzymes iNOS and COX-2, which stimulate the proliferation of colon cancer cells. In addition, the regulatory effects of Nrf2, which plays a critical role in mucosal inflammation, has been shown to be a mode of action of pterostilbene on the reduced risk of colon cancer23.
Pterostilbene may have potent modulatory effects on ageing
Again, it’s the antioxidant effects that are most well studied when it comes to the therapeutic use of pterostilbene in anti aging and longevity. The accumulation of free radicals causes widespread tissue damage, and reduces the function of the body over the lifespan.
Useful for its study in the mechanisms of ageing due to its short lifespan, one study used Caenorhabditis elegans, a common worm, to determine the effects of blueberry polyphenols on lifespan. While this 2006 study used a mixture of blueberry polyphenols to show the effects, the conclusion of the study suggested that the treatment with these compounds worked through other mechanisms, other than those targeting reactive oxygen species (ROS), and included increased resistance to heat stress, for example, which has been shown to have serious mortality risk for these organisms24.
While studies have found that resveratrol exerts its anti-ageing effects on the SIRT1 gene pathway, there is conflicting evidence when it comes to pterostilbene acting in the same way. Calorie restriction is evidenced as being one of the mechanisms of action of pterostilbene, where calorie restriction upregulates the SIRT1 pathway. There is strong evidence, however, to show that this pathway is in effect when using pterostilbene is used to protect from liver injury and ischemic hypoperfusion in muscle cells25,26.
Chronic inflammation has also been well studied in its effects on ageing, with a mismatch of pro- and anti-inflammatory pathways resulting in tissue damage and reduced ability of organs and body systems to function. The anti-inflammatory pathways of pterostilbene likely work through the AMPK and SIRT1 pathways, which reduces the release of inflammatory molecules, modulates inflammatory activities and regulates immune function aloof which have a protective role on the typical effects of aging27.
Human studies are in their infancy, but show promise
UVB irradiation is a well-known cause of skin damage across multiple species, and is associated with the formation of highly oxidative molecules, which offers a perfect model to study the effects of antioxidants. In human skin, there are complex antioxidant mechanisms that are in effect that aim to protect against the production of reactive oxygen species (ROS). The pathway involves the compounds Nrf2 and the antioxidant response element (ARE), both of which are recognised as central defense mechanisms against oxidative stress. When cells are treated with pterostilbene, it has been shown in studies, like that which was conducted in 2017 on human skin cells, that the compound enhances the action of Nrf2, which upregulates the ARE genetic pathway. In this way, pterostilbene has been shown to enhance cell survival through ROS homeostasis and subsequent suppression of inflammation and DNA damage28,29.
Pterostilbene has been tested for its safety profile for use in humans. In 2013, a double-blind, randomized control trial (the gold standard for human trials), concluded that pterostilbene is generally considered safe, where there were no adverse reactions in doses up to 250mg per day, which was the limit used in the study30. With that said, we eagerly await more clinical evidence, with studies being conducted in humans, which show the wide range of benefits for the therapeutic use of pterostilbene in a multitude of age-related diseases.
Selection of studies used for this article:
- Nagao, K., Jinnouchi, T., Kai, S., and Yanagita, T. (2017) Pterostilbene, a dimethylated analog of resveratrol, promotes energy metabolism in obese rats. J. Nutr. Biochem. 43, 151–155.
- Kapetanovic, I.M., Muzzio, M., Huang, Z. et al. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol (2011) 68: 593.
- Kapetanovic I., et al. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol. 2011 Sep; 68(3):593-601.
- Riche, D. M., McEwen, C. L., Riche, K. D., Sherman, J. J., Wofford, M. R., et al. (2013) Analysis of safety from a human clinical trial with pterostilbene. J. Toxicol. 2013, 463595.
- Kasiotis, K. M., Pratsinis, H., Kletsas, D., & Haroutounian, S. A. (2013). Resveratrol and related stilbenes: Their anti-aging and anti-angiogenic properties. Food and Chemical Toxicology, 61, 112–120.
- Li, Y.-R., Li, S., & Lin, C.-C. (2017). Effect of resveratrol and pterostilbene on aging and longevity. BioFactors, 44(1), 69–82.
- Rock C., et al. Reducing breast cancer recurrence with weight loss, a vanguard trial: the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial. Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial Group. Contemp Clin Trials. 2013 Mar; 34(2):282-95
- Alosi JA, McDonald DE, Schneider JS, Privette AR, McFadden DW. Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis. J Surg Res. 2010 Jun 15; 161(2):195-201.
- Priego S, Feddi F, Ferrer P, Mena S, Benlloch M, Ortega A, Carretero J, Obrador E, Asensi M, Estrela JM. Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism. Mol Cancer Ther. 2008 Oct; 7(10):3330-42.
- Adams L., et al. Whole blueberry powder modulates the growth and metastasis of MDA-MB-231 triple negative breast tumors in nude mice. J Nutr. 2011 Oct; 141(10):1805-12.
- Mannal P., et al. and tamoxifen show an additive effect against breast cancer in vitro. Am J Surg. 2010 Nov; 200(5):577-80.
- Chang, J., et al. Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease. Neurobiology of Aging. Volume 33, Issue 9, September 2012, Pages 2062-2071.
- Li, Q., et al. (2018). Pterostilbene inhibits amyloid-β-induced neuroinflammation in a microglia cell line by inactivating the NLRP3/caspase-1 inflammasome pathway. Journal of Cellular Biochemistry, 119(8), 7053–7062.
- Park ES, Lim Y, Hong JT, Yoo HS, Lee CK, Pyo MY, Yun YP. Pterostilbene, a natural dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell proliferation by blocking Akt-dependent pathway. Vascul Pharmacol. 2010 Jul-Aug; 53(1-2):61-7.
- Zhang L, Cui L, Zhou G, Jing H, Guo Y, Sun W. Pterostilbene, a natural small-molecular compound, promotes cytoprotective macroautophagy in vascular endothelial cells. J Nutr Biochem. 2013 May; 24(5):903-11.
- Ahmet I., et al. Blueberry-enriched diet protects rat heart from ischemic damage. PLoS One. 2009 Jun 18; 4(6):e5954.
- Park E., et al. Pterostilbene, a natural dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell proliferation by blocking Akt-dependent pathway. Vascul Pharmacol. 2010 Jul-Aug; 53(1-2):61-7.
- Sun, H., et al. (2019). Antidiabetic effects of pterostilbene through PI3K/Akt signal pathway in high fat diet and STZ-induced diabetic rats. European Journal of Pharmacology, 172526.
- Wang Y., et al. Effects of blueberry on hepatic fibrosis and transcription factor Nrf2 in rats. World J Gastroenterol. 2010 Jun 7; 16(21):2657-63.
- Wang Y., et al. Effect of blueberry on hepatic and immunological functions in mice. Hepatobiliary Pancreat Dis Int. 2010 Apr; 9(2):164-8.
- Kim J., et al. Pterostilbene from Vitis coignetiae protect H2O2-induced inhibition of gap junctional intercellular communication in rat liver cell line. Food Chem Toxicol. 2009 Feb; 47(2):404-9.
- Pan M., et al. Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Carcinogenesis. 2009 Jul; 30(7):1234-42.
- Pterostilbene is more potent than resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (Nrf2)-mediated antioxidant signaling pathway.
- Wilson, M. A., Shukitt-Hale, B., Kalt, W., Ingram, D. K., Joseph, J. A., et al. (2006) Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell 5, 59–68.
- Liu, X., Yang, X., Han, L., Ye, F., Liu, M., et al. (2017) Pterostilbene alleviates polymicrobial sepsis-induced liver injury: possible role of SIRT1 signaling. Int Immunopharmacol 49, 50–59.
- Cheng, Y., Di, S., Fan, C., Cai, L., Gao, C., et al. (2016) SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury. Apoptosis 21, 905–916.
- Li, Y., et al. (2017). Effect of resveratrol and pterostilbene on aging and longevity. BioFactors, 44(1), 69–82. doi:10.1002/biof.1400
- Chiou YS, Tsai ML, Nagabhushanam K, Wang YJ, Wu CH, Ho CT, Pan MH. Pterostilbene is more potent than resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (Nrf2)-mediated antioxidant signaling pathway. J Agric Food Chem. 2011 Mar 23; 59(6):2725-33.
- Li, H., et al. Pterostilbene protects against UVB-induced photo-damage through a phosphatidylinositol-3-kinase-dependent Nrf2/ARE pathway in human keratinocytes. Redox Report Communications in Free Radical Research. Volume 22, 2017 – Issue 6. 2017. 501-507.
- Riche, D., et al. Analysis of Safety from a Human Clinical Trial with Pterostilbene. Journal of Toxicology. Volume 2013, Article ID 463595, 5 pages.