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Fine-Tuning Your Longevity Genes

The nearly universal human desire to preserve youth can often motivate people to make major lifestyle changes or try the latest wonder supplement.  But is it really possible to slow the rate of aging with current knowledge and technology?  I argue herein that aging can be dramatically slowed by fine-tuning your longevity genes.  Indeed, scientific research carried out in the last 20 years has shown that lifespan can be readily modulated by a variety of genetic or dietary strategies.

In this article, I describe our efforts at Genescient LLC in Irvine, CA to develop strategies to delay aging and age-related disease.  Genescient’s primary business focus is on the development of pharmaceuticals for age-related diseases, but in conjunction with its spinoff firm Life Code LLC, it has provided testing services for the development of nutraceuticals based on its unique genomics platform.  Our findings can be summarized as follows:

  1. Aging is linked to altered expression in more than a hundred genes;
  2. We employed artificial intelligence algorithms combined with animal longevity assays to screen for wide-spectrum herbal extracts that extend lifespan;
  3. We succeeded in doubling animal lifespan using a novel class of nutrigenomic supplements that modulate genes involved in both aging and age-related disease.

What Are the Main Effects of Aging?

Fig. 1: Aging causes an exponential increase in the annual mortality rate. The actual decline in function with age occur at the cell, organ, and systemic levels, but the impacts of this decline can differ with the individual’s genes and environment. The net result of aging in an animal population is a progressive increase in all-cause mortality and morbidity. In the case of humans, all-cause mortality is known to double every eight years after sexual maturity until it reaches an annual mortality rate plateau of about 50% over 105 years of age.

All grafted data under 110 years are from the Social Security Administration Death Master File, while data on 110 to 119 year olds are from validated human super-centenarians from the website www.grg.org.

Why Do We Age?

All life forms on earth have evolved through natural selection, which selects the best genotype for fitness in a particular ecological niche.  In 1952 the British Nobel zoologist Peter Medawar proposed that aging is the simple result of the failure of natural selection to maintain fitness in older animals with declining fertility. As fertility wanes, then the chances to correct inappropriate gene expression via natural selection also decline, generating the aging phenotype.  Thus, according to Medawar’s hypothesis, aging is indirectly caused by the declining forces of natural selection to select the best fitness genes for the aged animal as reproductive capacity declines. In 1957, George Williams further developed Medawar’s evolutionary theory of aging by introducing the concept of antagonistic pleiotropy, wherein a gene may promote fitness in young fertile animals (and thus be selected for) but become a liability late in life leading to a subsequent decline in fitness.  Modern versions of Medawar’s and William’s evolutionary theories of aging are still widely believed today by most experts in aging science, as the theory fits well with the immense body of literature showing that natural selection is responsible for virtually all of the phenotypes present in the diverse species observed in Nature.  Evolution appears to evolve a life history for each species that is best adapted to its ecological niche.

Besides its sound theoretical basis in the well-known mechanisms of natural selection, the Evolution Theory of Aging has also been directly tested in Drosophila melanogaster by Michael Rose (UCI Professor and cofounder of Genescient).  If the Evolution Theory of Aging is correct, Dr. Rose predicted that he should be able to select populations of long-lived animals by simply selecting for reproductive longevity.  To carry out his longevity experiment, Dr. Rose started with 5 lines of wild type Drosophila flies and selected for reproductive longevity over a 27-year period.  Dr. Rose finally obtained robust Methuselah flies with a demonstrated lifespan of some 3 to 4 times that found in the non-selected control lines, while retaining fertility and sexual vitality. Genescient has carried out several independent experiments to verify that these Methuselah flies are indeed long lived compared to wild type flies.  As Genescient’s VP of R&D, I carefully monitored the most recent comparative lifespan experiment done in 2010 (Fig. 2).  The Methuselah flies (O populations) far outlive their unselected wild type fly B populations.  The selected Methuselah O flies have some 3 or 4 times longer mean lifespan than the non-selected wild type B flies (Fig. 2).  This selection experiment is a dramatic verification that evolution modulates the aging process.

 

 

Fig. 2: Breeding Drosophila for late reproduction leads to much longer lived flies. The result is as predicted by the Evolution Theory of Aging.

 

 

 

Studying gene expression in the wild type and Methuselah flies, Genescient has shown that several hundred genes have an altered expression in the Methuselah flies.  In late 2010, Genescient sequenced the DNA of the wild type and Methuselah flies and again found that more than a hundred genes appear to be altered in the long-lived Methuselah flies.

These experimental results are fully consistent with the Evolution Theory of Aging, which predicts that aging leads to poorly functioning organisms as natural selection for optimal gene function wanes with age.  In summary, we age because of the declining force of natural selection in adult life, which leads to unfit gene expression with age.

Developing Nutraceuticals That Can Extend Mean and Maximum Lifespan

If there are hundreds of genes that function poorly as we age, then one possible anti-aging strategy is to utilize wide-spectrum nutraceuticals to modify gene expression to a state consistent with greater longevity.  Note that the ideal gene expression pattern is not identical to youthful gene expression, as some of the youthful gene expression is inconsistent with longevity (e.g. genes promoting rapid growth that can lead to cancer).

To develop potential wide-spectrum antiaging nutraceuticals, Genescient initially set out to identify nutraceutical compounds that would target as many of the complementary longevity pathways as possible and thereby extend Drosophila lifespan.  Unfortunately, none of the single compound nutraceuticals tested appeared to significantly extend fly lifespan in our longevity screens.  The typically poor longevity effects of single compounds argue against the use of drug-like therapeutics directed to a single target for longevity treatments.

At this point, I decided to test mixtures of medicinal herbal extracts, as these have had a long history of success in Chinese and Indian traditional medicine and are known to have a wide spectrum of positive effects in humans.  To affect as many longevity genes as possible, I focused on complementary herbal extracts that have antioxidant, anti-inflammatory, and metabolic potential (known factors in driving aging) along with a positive effect on longevity genes and a proven history of use in traditional herbal medicine to treat a wide spectrum of diseases.

In selecting a group of herbal extracts, I did not take the traditional route of choosing an existing herbal mixture or the normal scientific route of choosing a mix of herbal extracts that target a particular disease or target.  While there are many claims that a particular herbal extract is “anti-aging”, I found that these claims were too anecdotal to be believed.  The screen for herbal extracts I used was novel in several ways.  First, I tried to identify the best wide-spectrum herb in Chinese, Indian, or Western medicine based on its long term traditional use and data indicating that the herbal extract can target multiple longevity genes identified by Genescient or by other research groups.

In Chinese traditional medicine, Astragalus membranaceus (Huang Qi) appeared to be the best Chinese herb because of its many traditional uses and recent studies demonstrating stem cell activation and inhibition of mTOR. The mTOR inhibition has extended mouse mean lifespan by 33%.  In traditional Chinese medicine astragalus is considered a true tonic that can strengthen debilitated patients and increase resistance to disease in general. Modern herbal treatments with Astragalus membranaceus root (often in concert with other herbs) are partly based on clinical trials showing benefits in strengthening immune function during viral (e.g. chronic hepatitis) or bacterial infection or in those individuals undergoing dialysis for kidney failure.  Clinical trials at the US National Cancer Institute and other world centers have indicated that Astragalus can strengthen immunity and improve survival in some individuals with cancer.  In western herbal medicine, Astragalus root is used to enhance immunity and to help in wound healing.  Astragalus compounds have also been shown to stimulate stem cells, promote peripheral nerve regeneration in rats, and inhibit mTOR (a major longevity gene shown by extensive government studies to extend lifespan in mice).

In looking for the best herb in the Indian Ayurvedic medicinal tradition, I soon focused on the potent anti-diabetic herb, Pterocarpus marsupium.  Crude extracts of Pterocarpus marsupium (Indian keno tree) bark naturally have high concentrations of pterostilbene (more than 4% by weight and extraction can get this level much higher) and have been used as a traditional herbal treatment for diabetes in India for thousands of years.  More recent studies in animals show potent anti-diabetic activity.  Published studies have also shown that pterostilbene is a potent anticancer compound.  For example, pterostilbene, an analog of resveratrol, has dose-dependent anticancer activity in five cancer cell lines.  As expected, pterostilbene is known to affect most or all of the longevity genes targeted by resveratrol, but has far greater stability and efficacy.

As an herbal medicine, Pterocarpus marsupium is popular in India for its diverse health benefits.   Besides diabetes, the herb is also reported to cure a wide spectrum of ailments like skin diseases, fractures, bruises, constipation, hemorrhages, and rheumatoid arthritis.  These diverse health benefits of Pterocarpus marsupium make it a clear favorite to include in a preventive herbal cocktail along with Astragalus.

Having selected two of the biggest stars in the traditional herbal medicines of China and India, I looked for an effective herb with wide-spectrum health effects from the Western herbal tradition.  In this case, pine bark proanthocyanidins stand out as the best wide-spectrum herbal extracts in the Western herbal medicine tradition.  Proanthocyanidins are polymer chains of flavonoids (flavan-3-ols) that were discovered by Jacques Masquelier in 1948 and have been a major therapeutic supplement in Europe since the 1980s.  Most of the research and commercial success with proanthocyanidins has come from extracts of a French maritime pine bark called Pycnogenol (65 to 75% proanthocyanidins) and various grape seed extracts (80-90% proanthocyanidins).

One interesting claim of health benefits from proanthocyanidins is the hypothesis that they are responsible for the “French Paradox”, wherein the French tend to have much reduced rates of cardiovascular disease compared to other Western countries on a high-fat diet because of their high intake of red wine made with grapes.  Besides their cardiovascular effects, Oligo-Proanthocyanidins (OPCs as attached units of proanthocyanidins are called) are known to have many other health benefits.  For example, OPCs stabilize collagen and elastin, which are two essential proteins in connective tissues from blood vessels, muscles, and skin.  OPCs are reported to reduce genetic mutations, so they have some anticancer benefits.  OPCs have also been shown in clinical trials to promote blood flow and endothelial nitric oxide while reducing edema, capillary fragility, and damage from pollution, toxins, and cigarette smoke.  These diverse health benefits make Pine Bark proanthocyanidins another perfect candidate to combine with wide-spectrum herbal extracts from Astragalus membranaceus and Pterocarpus marsupium bark.

To round out the above herbs, I wanted an herbal compound that provided neural protection in the brain.  L-theanine (also known as gamma-glutamylethylamide, or 5-N-ethyl-glutamine) is an uncommon amino acid found preferentially in green tea.  Theanine is an analog of glutamine and glutamate and can cross the blood-brain barrier to directly affect the brain.  Among its psychoactive properties, theanine is reported to reduce mental stress and improved cognition and mood via its binding to the GABA brain receptors in the parasympathetic nervous system.  Thus, theanine appears to increase the overall level of the brain inhibitory transmitter GABA and is reported to promote alpha wave production in the brain.  Theanine also increases brain dopamine concentrations and has significant affinities for the AMPA and NMDA receptors.  The NMDA receptors help control memory and synaptic plasticity.  Theanine may also have positive effects on serotonin levels to promote restful sleep.  In rats, theanine is neuroprotective.  All of these neuroprotective properties of L-theanine make it a strong complementary addition to the three essential core herbs of the herbal mix.  We named the final 4-herb mix StemCell 100, because of its positive effects on adult stem cells and have filed a patent application on this wide-spectrum nutraceutical.

Drosophila Longevity Studies Using Treatment with StemCell 100

The current StemCell 100 herbal blend has gone through extensive longevity testing with Drosophila fruit flies.  The Drosophila longevity study (see Figs 3 and 4 below) included three cages of fruit flies that were treated with StemCell 100 (T1 to T3) and three cages that were untreated controls (C1 to C3).  Each cage started with 500 fruit flies including 250 males and 250 females.  The experiment showed that mean lifespan more than doubled with a 123% increase.  That would be like the average human living to 167 years of age! While fruit flies are not people, they are more like us than you might think.  Drosophila has a heart and circulatory system, and the most common cause of death is heart failure.  Like humans and other mammals (e.g. mice), it is quite difficult to increase their lifespan significantly. The doubling of mean lifespan by StemCell 100 outperforms every lifespan enhancing treatment ever tested in flies – including experiments using genetic modification and dietary restriction.

Fig. 3: Mean lifespan of StemCell 100 treated and control flies

The longest living fruit fly receiving StemCell 100 lived 89 days compared to the longest living untreated control which lived 48 days.  That is an increase in maximum lifespan of 85% which is the equivalent of a person living to be 191 years old! It is possible that the single longest living fruit fly lived longer for other reasons such as genetic mutation; however, there were many others that lived almost as long so it was not just an aberration.  For example, the oldest 5% of the treated fruit flies lived 77% longer than the oldest 5% of the control group (see Fig. 4 below).

Fig. 4: Lifespan of last 5% survivors using StemCell 100 treated and control flies

Pilot Field Trial on Human Volunteers

A small clinical field trial with six healthy individuals was run using StemCell 100 for a period of four months (Fig. 5).  The average HDL (good cholesterol) gain with treatment was 11.4 mg/dL or 25%.

Fig. 5: StemCell 100 Field Trial: Blood tests were performed before and after treatment with StemCell 100 to see if the treatment changed cholesterol or other blood chemistry profiles.  Liver function and blood chemistry were the same before and after treatment in all participants, but there were small reductions in total cholesterol and LDL (bad-cholesterol) with the herbal treatment.  The biggest surprise was the relatively large increases in HDL (good cholesterol) in all 6 test subjects – even the three individuals that were on statins (participants 1*, 2*, and 5*) showed large increase in HDL cholesterol.

We also checked four individuals before and after StemCell 100 treatment for changes in blood pressure (Fig. 6).  There was a relatively large reduction in systolic and diastolic blood pressure.  The average Systolic BP (red) dropped 12 mm of Hg with treatment, while the average Diastolic BP (blue) dropped 10 mm of Hg.  High HDL cholesterol and reduced blood pressure are independent indicators of longevity, so these results suggest that the StemCell 100 may reduce all-cause mortality in humans, as is the case for Drosophila.

Fig. 6: Blood Pressure Changes: Four of the 6 above field trial participants also were checked for changes in systolic and diastolic blood pressure after treatment with StemCell 100.  The observed reductions with StemCell 100 are similar to those found with anti-hypertensive proscription drugs such as the ACE inhibitors.

 

Conclusion

Genescient used genomic studies in Drosophila to determine that aging is modulated by over a hundred genes.  We then used animal longevity assays to screen for nutrigenomic supplements that extend lifespan.  We succeeded in doubling Drosophila lifespan using a novel class of wide-spectrum herbal supplements that modulate genes involved in both aging and age-related disease.  The doubling of mean lifespan by StemCell 100 outperforms every lifespan enhancing treatment ever tested in Drosophila – including experiments using genetic modification and dietary restriction.  With this successful demonstration of the power of Genescient’s genomic R & D system, Genescient’s proprietary genomic techniques can now be applied to developing wide-spectrum drug combinations for the age-related diseases.

To market StemCell 100, Genescient entered a joint venture with Centagen. (a co-creator of the StemCell 100 formulation) to form Life Code LLC.  Genescient and Centagen have spent two years in extensive animal and human testing to optimize the herbal formulation in StemCell 100.  The dosage and quality of the individual components emerged as critical factors in providing safety and efficacy.  With the development complete, StemCell 100 is now available. [http://www.lifecoderx.com/ ]

While the four herbal extracts in StemCell 100 formulation have tremendous synergistic properties when properly manufactured in the optimized formulation, each of the four herbal extracts in StemCell 100 – when taken separately – have exceptional records in promoting animal and human health.  For example, the individual components of StemCell 100 help support:

  1. Adult stem cell rejuvenation [1-4].
  2. A healthy cardiovascular system [5-8].
  3. Healthy blood glucose levels for those already in the normal range [9-13].
  4. Healthy blood pressure levels for those already in the normal range [14-15].
  5. Healthy cholesterol levels for those already in the normal range [9, 16-15].
  6. Younger looking skin [18-24].
  7. Better learning and focus [25-30].
  8. More endurance with vigorous exercise [31-35].
  9. A healthy immune system [31-32, 36-39].
  10. Healthy breasts, colon, pancreas, and prostate [40-46].

References

1.    Yu, Q., Y.S. Bai, and J. Lin, [Effect of astragalus injection combined with mesenchymal stem cells transplantation for repairing the Spinal cord injury in rats]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2010. 30(4): p. 393-7.
2.    Xu, C.J., et al., [Effect of astragalus polysaccharides on the proliferation and ultrastructure of dog bone marrow stem cells induced into osteoblasts in vitro]. Hua Xi Kou Qiang Yi Xue Za Zhi, 2007. 25(5): p. 432-6.
3.    Xu, C.J., et al., [Effects of astragalus polysaccharides-chitosan/polylactic acid scaffolds and bone marrow stem cells on repairing supra-alveolar periodontal defects in dogs]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006. 31(4): p. 512-7.
4.    Zhu, X. and B. Zhu, [Effect of Astragalus membranaceus injection on megakaryocyte hematopoiesis in anemic mice]. Hua Xi Yi Ke Da Xue Xue Bao, 2001. 32(4): p. 590-2.
5.    Qiu, L.H., X.J. Xie, and B.Q. Zhang, Astragaloside IV improves homocysteine-induced acute phase endothelial dysfunction via antioxidation. Biol Pharm Bull, 2010. 33(4): p. 641-6.
6.    Araghi-Niknam, M., et al., Pine bark extract reduces platelet aggregation. Integr Med, 2000. 2(2): p. 73-77.
7.    Rohdewald, P., A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther, 2002. 40(4): p. 158-68.
8.    Koch, R., Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytother Res, 2002. 16 Suppl 1: p. S1-5.
9.    Rimando, A.M., et al., Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agric Food Chem, 2005. 53(9): p. 3403-7.
10.    Manickam, M., et al., Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod, 1997. 60(6): p. 609-10.
11.    Grover, J.K., V. Vats, and S.S. Yadav, Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate. Diabetes Obes Metab, 2005. 7(4): p. 414-20.
12.    Mao, X.Q., et al., Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model. Acta Pharmacol Sin, 2007. 28(12): p. 1947-56.
13.    Schafer, A. and P. Hogger, Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract, 2007. 77(1): p. 41-6.
14.    Kwak, C.J., et al., Antihypertensive effect of French maritime pine bark extract (Flavangenol): possible involvement of endothelial nitric oxide-dependent vasorelaxation. J Hypertens, 2009. 27(1): p. 92-101.
15.    Xue, B., et al., Effect of total flavonoid fraction of Astragalus complanatus R.Brown on angiotensin II-induced portal-vein contraction in hypertensive rats. Phytomedicine, 2008.
16.    Mizuno, C.S., et al., Design, synthesis, biological evaluation and docking studies of pterostilbene analogs inside PPARalpha. Bioorg Med Chem, 2008. 16(7): p. 3800-8.
17.    Sato, M., et al., Dietary pine bark extract reduces atherosclerotic lesion development in male ApoE-deficient mice by lowering the serum cholesterol level. Biosci Biotechnol Biochem, 2009. 73(6): p. 1314-7.
18.    Kimura, Y. and M. Sumiyoshi, French Maritime Pine Bark (Pinus maritima Lam.) Extract (Flavangenol) Prevents Chronic UVB Radiation-induced Skin Damage and Carcinogenesis in Melanin-possessing Hairless Mice. Photochem Photobiol, 2010.
19.    Pavlou, P., et al., In-vivo data on the influence of tobacco smoke and UV light on murine skin. Toxicol Ind Health, 2009. 25(4-5): p. 231-9.
20.    Ni, Z., Y. Mu, and O. Gulati, Treatment of melasma with Pycnogenol. Phytother Res, 2002. 16(6): p. 567-71.
21.    Bito, T., et al., Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to human keratinocytes by inhibiting inducible ICAM-1 expression. Free Radic Biol Med, 2000. 28(2): p. 219-27.
22.    Rihn, B., et al., From ancient remedies to modern therapeutics: pine bark uses in skin disorders revisited. Phytother Res, 2001. 15(1): p. 76-8.
23.    Saliou, C., et al., Solar ultraviolet-induced erythema in human skin and nuclear factor-kappa-B-dependent gene expression in keratinocytes are modulated by a French maritime pine bark extract. Free Radic Biol Med, 2001. 30(2): p. 154-60.
24.    Van Wijk, E.P., R. Van Wijk, and S. Bosman, Using ultra-weak photon emission to determine the effect of oligomeric proanthocyanidins on oxidative stress of human skin. J Photochem Photobiol B, 2010. 98(3): p. 199-206.
25.    Haskell, C.F., et al., The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol, 2008. 77(2): p. 113-22.
26.    Owen, G.N., et al., The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci, 2008. 11(4): p. 193-8.
27.    Yamada, T., et al., Effects of theanine, a unique amino acid in tea leaves, on memory in a rat behavioral test. Biosci Biotechnol Biochem, 2008. 72(5): p. 1356-9.
28.    Jia, R.Z., et al., [Neuroprotective effects of Astragulus membranaceus on hypoxia-ischemia brain damage in neonatal rat hippocampus]. Zhongguo Zhong Yao Za Zhi, 2003. 28(12): p. 1174-7.
29.    Nathan, P.J., et al., The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother, 2006. 6(2): p. 21-30.
30.    Nobre, A.C., A. Rao, and G.N. Owen, L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr, 2008. 17 Suppl 1: p. 167-8.
31.    Murakami, S., et al., Effects of oral supplementation with cystine and theanine on the immune function of athletes in endurance exercise: randomized, double-blind, placebo-controlled trial. Biosci Biotechnol Biochem, 2009. 73(4): p. 817-21.
32.    Kawada, S., et al., Cystine and theanine supplementation restores high-intensity resistance exercise-induced attenuation of natural killer cell activity in well-trained men. J Strength Cond Res, 2010. 24(3): p. 846-51.
33.    Hu, Y.C. and J.Y. Hou, [Effect of zhimu and huangqi on cardiac hypertrophy and response to stimulation in mice]. Zhongguo Zhong Yao Za Zhi, 2003. 28(4): p. 369-74.
34.    Chen, K.T., et al., Reducing fatigue of athletes following oral administration of huangqi jianzhong tang. Acta Pharmacol Sin, 2002. 23(8): p. 757-61.
35.    Luo, H.M., R.H. Dai, and Y. Li, [Nuclear cardiology study on effective ingredients of Astragalus membranaceus in treating heart failure]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 1995. 15(12): p. 707-9.
36.    Sugiura, H., et al., [Effects of exercise in the growing stage in mice and of Astragalus membranaceus on immune functions]. Nippon Eiseigaku Zasshi, 1993. 47(6): p. 1021-31.
37.    Cho, W.C. and K.N. Leung, In vitro and in vivo anti-tumor effects of Astragalus membranaceus. Cancer Lett, 2007. 252(1): p. 43-54.
38.    Kong, X., et al., Effects of Chinese herbal medicinal ingredients on peripheral lymphocyte proliferation and serum antibody titer after vaccination in chicken. Int Immunopharmacol, 2004. 4(7): p. 975-82.
39.    Takagi, Y., et al., Combined administration of (L)-cystine and (L)-theanine enhances immune functions and protects against influenza virus infection in aged mice. J Vet Med Sci, 2010. 72(2): p. 157-65.
40.    Tin, M.M., et al., Astragalus saponins induce growth inhibition and apoptosis in human colon cancer cells and tumor xenograft. Carcinogenesis, 2007. 28(6): p. 1347-55.
41.    Mannal, P.W., et al., Pterostilbene inhibits pancreatic cancer in vitro. J Gastrointest Surg, 2010. 14(5): p. 873-9.
42.    Paul, S., et al., Dietary intake of pterostilbene, a constituent of blueberries, inhibits the {beta}-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats. Carcinogenesis, 2010.
43.    Paul, S., et al., Anti-inflammatory action of pterostilbene is mediated through the p38 mitogen-activated protein kinase pathway in colon cancer cells. Cancer Prev Res (Phila Pa), 2009. 2(7): p. 650-7.
44.    Suh, N., et al., Pterostilbene, an active constituent of blueberries, suppresses aberrant crypt foci formation in the azoxymethane-induced colon carcinogenesis model in rats. Clin Cancer Res, 2007. 13(1): p. 350-5.
45.    Chakraborty, A., et al., In vitro evaluation of the cytotoxic, anti-proliferative and anti-oxidant properties of pterostilbene isolated from Pterocarpus marsupium. Toxicol In Vitro, 2010. 24(4): p. 1215-28.
46.    Alosi, J.A., et al., Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis. J Surg Res, 2010. 161(2): p. 195-201.