Resveratrol — What is it?
This polyphenolic compound is argued by some as an antioxidant that may extend lifespan. This has been mentioned by several public figures, including Andrew Huberman and David Sinclair. One Huberman Lab podcast episode included a Q&A session between the two figures, where they mentioned Resveratrol is known as a substance that can trigger the activity of Sirtuin genes, which can lead to the formation of Sirtuin proteins (specifically SIRT6). Concomitant in slowing the aging process, NAD levels are known to decline as we age or become obese. SIRT levels diminish as NAD levels deplete (Andrew Huberman). (watch from 56:45)
However, this speculation does not have enough human clinical research to back up these claims. Much of the study on Resveratrol lead to potential claims of its potency in regulating telomere shortening and other age-accelerating mechanisms.
Resveratrol is found in red wine, peanuts, grape skin, blueberries, and dark chocolate.
The function:
A few preliminary studies with Resveratrol show the compound to be an activator of deacetylases. Specifically, a few SIRT proteins (SIRT1, SIRT6, and SIRT7) are proteins involved in DNA repair. As mentioned in my previous article about homologous recombination in place of its role in CRISPR repair, SIRT1 promotes the process in human cells and is involved in recombinational repair. Meanwhile, SIRT6, when deficient in mice, leads to an accelerated degenerative aging-like phenotype while playing a role in the base excision repair of DNA damage (Hubbard et al.). SIRT7 is required for the repair of 2x-stranded DNA breaks via the non-homologous end joining (NHEJ) mechanism, also detailed in my written CRISPR articles.
Hubbard et al. claim on Resveratrol that the compound can mimic caloric restriction, which in animal studies can upregulate autophagy that leads to the prevention of heart disease and Type II Diabetes. Known as a vasodilator, Blood pressure can also decrease in turn. Glutathione, which can help prevent free radical damage, is also promoted by Resveratrol (Galiniak et al.).
The positive effects of Resveratrol are dose-dependent. If exposed to an excess amount of Resveratrol, it can act as an estrogen receptor sensitizer, elevated BUN, elevated creatinine, elevated WBC count, nephromegaly, along with reduced Hematocrit. Too much estradiol may result in acne, loss of sex drive, osteoporosis, and depression. Very high levels (3000 mg/day) can increase the risk of uterine and breast cancer (Nichols).
The Galiniak et al. review of Resveratrol also drew upon its ability to inhibit cytochrome c release from the inner mitochondrial membrane, which can lead to enhanced ATP (energy) production. Elevated membrane potential is a consequence, which allows the cell to produce more energy for its physiological processes. In obese mice fed a high-fat diet, Resveratrol is shown to reduce oxidative stress and inflammation as well.
Resveratrol may also serve as a neuroprotective benefit. Galiniak et al. shared that the compound can reduce neurodegeneration specifically in the murine (mouse) cerebral cortex, involving many different functions. Notably, Tao et al. showed that Resveratrol can alleviate neuropathic pain in mice by repressing the expression of proinflammatory cytokines and increasing IL-10 (Galiniak et al.).
The aging:
Generally, we can see that aging is a natural cycle of cellular senescence. Apoptosis, which is programmed cell death, is also a heavy influence on the aging process. Oxidative stress upregulates this process, while the likelihood of DNA mutations, mis-repair, or enhanced cellular proliferation (cancer) can lead to accelerated aging. Oxidative stress is defined as an imbalance between the generation of reactive oxygen species and antioxidant defense, where there is a deficit in antioxidant defense. Enhanced oxidative stress damages macromolecules, impairment their functions, and underlying many age-related diseases, including cancer, diabetes, CKD, cardiovascular, and neurodegenerative diseases. Induces inflammation, dysregulation of mitochondria, and cell death (Tan et al).
Aging also can lead to a higher incidence of inflammation, since senescent and adipose tissue are both capable of secreting inflammatory markers. Resveratrol is known to suppress IL-6 and TNF-alpha transcription and translation, owing to a reduced cytokine response from macrophages, without inducing cytotoxicity. Additionally, it can inhibit Toll-like receptors (TLRs) from secreting proinflammatory cytokines. Resveratrol shows protective activity against ischemia-reperfusion injury by inhibiting mast cell degranulation, and decreasing apoptosis of intestinal epithelial cells, which serves to prevent overall organ dysfunction. Taken altogether, Resveratrol can reduce inflammation markers (Galiniak et al.).
The biggest influence Resveratrol may have on aging refers to its impact on glycation. Glycation is a nonenzymatic reaction between proteins and reducing sugars, leading to Advanced Glycation end products (AGEs). These AGEs accumulate and cause damage at the cellular level, which includes altering protein structure, thereby altering protein function. Higher levels of glycation lead to a higher incidence of diabetes, myasthenia gravis, or neurodegenerative diseases such as neuropathy (Galiniak et al.).
Glycation specifically produces dicarbonyl compounds methylglyoxal and glyoxal, known to produce oxidative stress on the body. Polyphenolic compounds do have antiglycation properties, which classify Resveratrol (Galiniak et al.). Chemically, the hydroxyl substituents that characterize the Resveratrol structure can react with the dicarbonyl compounds, hydrolyzing them to alter the structure and thereby function of the dicarbonyl compounds. As such, Resveratrol’s impact on Glycation can be further investigated to understand how present glycation is in our bodies.
Synergistic Effects:
Resveratrol can enhance the effectiveness of Polymyxin B, used in Pseudomonas Aeruginosa infections. These infections normally cause cystic fibrosis (CF) in immunocompromised individuals. Since P. aeruginosa infections have resistance to most other antibiotics, it is difficult to treat patients with this infection.
In one study done by Qi et al., Resveratrol was shown to significantly enhance the antibiotic capability of Polymyxin B, an antibiotic that serves to attack the cell membrane of the bacterium. Since it is not advisable to increase the dosage of Polymyxin B due to the risk of certain side effects, Resveratrol can be used to supplement the prescription of Polymyxin B to enhance its effects in attacking the cell membrane.
Fig.1 shows how the CFU (colony forming units of bacteria, a measure of how much bacteria is present on a plate) diminishes among all but one strain of P. aeruginosa. Meanwhile, only including either the Resveratrol or Polymyxin B in vitro at a level of 4 µg/mL did not yield a comprehensive defense against the bacteria, failing to react to some level. The synergistic presence of 64 µg/mL Resveratrol and the 4 µg/mL Polymyxin B had the greatest effect in halting bacterial growth. Later, in the discussion, it was found that resveratrol concentration lower than 32 µg/mL has no synergistic effect, which is important since the highest blood-stream concentration of resveratrol that can be achieved is only 534 ng/mL (Qi et al.).
Is it possible to somehow utilize these results in medicine? Frankly, that is out of my current scope, and I cannot say. But it does beg the question of whether Resveratrol can work with other antibiotics and provide some sort of therapeutic purpose.
Conclusion:
There is not much support behind Resveratrol as a legitimate anti-aging, despite its effectiveness as an anti-glycation agent. Its function of Resveratrol a deacetylase ensures that the histones which wrap our DNA are bound more tightly, owing to less gene expression. Does this necessarily lead to an anti-aging pathway? It could mean less cell division, which may inhibit cell growth, which could lead to less aging as a result. But for people like Shahid Behesti, Resveratrol treatment was shown to decrease telomere size and inflict DNA damage more on lung cancer patients (Resveratrol). Additionally, cells were found to become more sensitive to radiation in patients with prostate cancer.
The manifold functions of Resveratrol make it a compound to consider studying further, however. The impact it has on estrogen sensor receptors, glutathione, inhibiting innate immune system function in the hope of reducing inflammation, and even reducing the apoptosis of neuronal damage seem to place Resveratrol as a positive compound in positive ways. Seeing its impact on polymyxin B in patients with Cystic Fibrosis also provides a potential treatment that can be developed further.
In the end, I would not recommend supplementing with pure Resveratrol. However, the impact of free radicals should not go unnoticed, and it would be wise to study the effects of what oxidative stress can do on the body.
Works Consulted
Andrew Huberman. (2021, December 27). Dr. David Sinclair: The Biology of Slowing & Reversing Aging | Huberman Lab Podcast #52 [Video]. YouTube. https://www.youtube.com/watch?v=n9IxomBusuw&t=3842s
Eyster K. M. (2016). The Estrogen Receptors: An Overview from Different Perspectives. Methods in molecular biology (Clifton, N.J.), 1366, 1–10. https://doi.org/10.1007/978-1-4939-3127-9_1
Galiniak, S., Aebisher, D., & Bartusik-Aebisher, D. (2019). Health benefits of resveratrol administration. Acta Biochimica Polonica, 66(1), 13–21. https://doi.org/10.18388/abp.2018_2749
Grabowska, W., Sikora, E., & Bielak-Zmijewska, A. (2017). Sirtuins, a promising target in slowing down the ageing process. Biogerontology, 18(4), 447–476. https://doi.org/10.1007/s10522-017-9685-9
Hubbard, B. P., Gomes, A. P., Dai, H., Li, J., Case, A. W., Considine, T., Riera, T. V., Lee, J. E., E, S. Y., Lamming, D. W., Pentelute, B. L., Schuman, E. R., Stevens, L. A., Ling, A. J. Y., Armour, S. M., Michan, S., Zhao, H., Jiang, Y., Sweitzer, S. M., Sinclair, D. A. (2013). Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. Science, 339(6124), 1216–1219. https://doi.org/10.1126/science.1231097
Nichols, H. (2020, March 6). Everything you need to know about estrogen. Medical News Today. https://www.medicalnewstoday.com/articles/277177
Qi, L., Liang, R., Duan, J. et al. Synergistic antibacterial and anti-biofilm activities of resveratrol and polymyxin B against multidrug-resistant Pseudomonas aeruginosa. J Antibiot (2022). https://doi.org/10.1038/s41429-022-00555-1
Resveratrol: Anti Aging and Anti-Cancer Effects on the Human Body. (2020, July 24). Liv HEALTH. https://livhealth.com/resveratrol-anti-aging/
Smoliga, J. M., Baur, J. A., & Hausenblas, H. A. (2011). Resveratrol and health — A comprehensive review of human clinical trials. Resveratrol and Health — A Comprehensive Review of Human Clinical Trials, 55(8), 1129–1141. https://doi.org/10.1002/mnfr.201100143
Tan, B. L., Norhaizan, M. E., Liew, W. P. P., & Sulaiman Rahman, H. (2018). Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases. Frontiers in Pharmacology, 9. https://doi.org/10.3389/fphar.2018.01162
