What can we, the consumers, learn from the tragic failure of resveratrol hype?

Posted on February 24, 2022 by Dr. Cheng

What can we, the consumers learn from the tragic failure of resveratrol hype?

The heat of Resveratrol for antiaging started earlier this century after some research shows increasing an enzyme called SIRT2 doubles lifespan in yeast1,2, making people to anticipate lifespan extension of humans. SIRT2 gene is also suggested as the reason why people benefitted from calorie restrictions (fasting)3,4.  David Sinclair’s lab published a paper in 2003 that resveratrol extends lifespan of S. cerevisiae5.  But S. cerevisiae is a single cell organism, quite different from animals such as mice or humans. In 2006, Sinclair’s lab again showed resveratrol improves health and survival of obese mice to make them live almost as long as normal mice3.  David Sinclair co-founded a company called Sirtris Pharmaceuticals based on these findings. GSK later bought Sirtris for $720 million.  But then other researchers began to wonder why they couldn’t repeat Sinclair’s resveratrol results and the suspicion that the original data was flawed began to surface6. Activating sirtuins can extend lifespan of worms and flies, however their effects on aging are vulnerable to confounding genetical factors7. When these confounding factors are properly controlled, resveratrol’s effects on aging disappeared7. Besides, the benefits of calorie restriction have nothing to do with Sirt2 gene7. This is quite a blow to the scientific foundation of the claim that resveratrol could extend lifespan.  There is even some research to show that blocking Sir2 genes may extend lifespan8. It turns out that it’s not resveratrol that activated SIRT1 gene, it’s an artificial dye that was responsible for the Sirt1 gene activation, and resveratrol itself does not activate SIRT1 gene, reported by separate laboratories9,10. So by now, it’s clear that the observation of resveratrol activation of Sirt1 is a lab error. GSK’s $720M dollars investment was based on flawed lab data. A more recent study further shows that resveratrol’s effects are not by activation of SIRT gene but by “induction of low-level replicative stress”11. So resveratrol only “activates” SIRT gene under certain specific conditions in laboratory but not in vivo (inside human body). But GSK is not giving up without a fight. GSK is dumping more money on clinical trials of resveratrol12. But GSK is fighting an uphill battle: 1. Resveratrol is poorly absorbed; 2. The small amount that is absorbed is quickly destroyed at the liver (don’t forget resveratrol is a plant based chemical and there is “foreign” to our body. Our body naturally tends to defend against these “foreign” chemicals by destroying them in the liver. Plant chemicals that are not naturally existing in human are mostly toxins. At low doses, these plant toxins may induce some health benefits by causing “stress” related biological responses from our body. This process is called hormesis.); 3. Resveratrol activates Sirt gene only under very specific conditions that are not found usually in human bodies. GSK (Sirtris) developed a resveratrol derivative called SRT 501 which has a better absorption. There is an ongoing clinical trial of SRT50112. SRT501 was used as a treatment for patients with refractory or relapsed multiple myeloma. The clinical trial was terminated early due to severe side effects including nephrotoxicity13. Over 150 trials using resveratrol has been done with no clear clinical benefits14. Take this randomized, double blind and placebo controlled trial15. Resveratrol of up to 1000 mg for 16 weeks, but no effect on inflammation control was observed. Even worse, those received resveratrol showed an elevation of cholesterol levels. Resveratrol also blunts the positive effects of exercise training16,17.

The National Institute on Aging Interventions Testing Program (ITP) is a government agency responsible for testing of hopeful drugs. Resveratrol didn’t pass the criteria of the National Institute on Aging Interventions Testing Program (ITP). However, ITP was directly told to test resveratrol. ITP ran the resveratrol test 6 times, but all tests still showed negative results of resveratrol18. Over $2B was spent on resveratrol studies over the past 20 years without clear evidence that resveratrol is helpful to health. Facing the mounting evidence against his original hype that resveratrol is a “fountain of youth” from which he benefitted tremendously, he continues to defend his positions to the extend he began to tell lies19.

Important lessons that we, the consumers, should learn from this resveratrol saga/scandal are:

  1. Lab research results don’t equal to clinical results on humans. Scientific experiments are done under specific conditions, often different from those of humans.
  2. Health/medicine is such a vast field that most consumers don’t have the necessary training in the field to really understand these, often falling prey to these hypes.
  3. What can you do, as a consumer, to protect yourself from falling into prey? My advice is to find a medical doctor (not a basic scientist) who has education, training and experience in both basic science and clinical medicine, who puts patients’ health ahead of financial interests.

 

References:

  1. Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13, 2570–2580 (1999).
  2. Swaminathan, N. The Fountain of Youth at the Bottom of a Wine Bottle? Scientific American https://www.scientificamerican.com/article/the-fountain-of-youth-at/.
  3. Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).
  4. Lee, S.-H., Lee, J.-H., Lee, H.-Y. & Min, K.-J. Sirtuin signaling in cellular senescence and aging. BMB Rep 52, 24–34 (2019).
  5. Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
  6. Pezzuto, J. M. Resveratrol: Twenty Years of Growth, Development and Controversy. Biomol Ther (Seoul) 27, 1–14 (2019).
  7. Burnett, C. et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477, 482–485 (2011).
  8. Fabrizio, P. et al. Sir2 blocks extreme life-span extension. Cell 123, 655–667 (2005).
  9. Beher, D. et al. Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity. Chemical Biology & Drug Design 74, 619–624 (2009).
  10. Pacholec, M. et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285, 8340–8351 (2010).
  11. Benslimane, Y. et al. Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells. Mol Cell 79, 846-856.e8 (2020).
  12. Sirtris, a GSK Company. A Phase II, Open-Label, Clinical Study to Assess the Safety and Activity of SRT501 Alone or in Combination With Bortezomib in Patients With Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT00920556 (2018).
  13. Popat, R. et al. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br J Haematol 160, 714–717 (2013).
  14. Curry, A. M., White, D. S., Donu, D. & Cen, Y. Human Sirtuin Regulators: The ‘Success’ Stories. Front Physiol 12, 752117 (2021).
  15. Kjær, T. N. et al. No Beneficial Effects of Resveratrol on the Metabolic Syndrome: A Randomized Placebo-Controlled Clinical Trial. J Clin Endocrinol Metab 102, 1642–1651 (2017).
  16. Gliemann, L. et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol 591, 5047–5059 (2013).
  17. Olesen, J. et al. Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men. J Physiol 592, 1873–1886 (2014).
  18. Strong, R. et al. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68, 6–16 (2013).
  19. Brad Stanfield, MD. Resveratrol – The Unfortunate (& Scandalous) Story.
  20. Amjad, S. et al. Role of NAD+ in regulating cellular and metabolic signaling pathways. Molecular Metabolism 49, (2021).

 

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