Dr. Richard Cheng, Cheng Integrative Health Center

Highlights:

1. 95% of  melatonin in your is made inside your mitochondria (via Cytochrome C) in response to near-infrared radiation (NIR) from the sun.
2. Only 5% of melatonin is produced in your pineal gland at night.
3. Mitochondria are the powerhouse of our cells for energy production (in the form of ATP). Lots of free radicals are also produced as byproducts. Excessive free radicals, if not neutralized promptly, will cause damage to mitochondria and other cellular structures.
4. Mitochondrial dysfunction is observed in most, if not all, chronic diseases, esp. cancers, neurodegenerative diseases (Alzheimer’s, Parkinson’s), cardiovascular diseases, autoimmune diseases and diabetes.
5. Melatonin is a powerful antioxidant. Melatonin and other antioxidants, such as Vit C, Vit E and glutathione, protect the health of mitochondria and other cellular structures by neutralizing these excessive and harmful free radicals (reactive oxygen species, ROS).
6. Unfortunately, we usually don’t take melatonin during the day as it will make you sleep. So we need to get exposure to sunshine. Good news is that the NIR portion of sunshine is highly penetrable. You don’t need to necessarily be directly under the sun. Even in the shade, under the tree or around lots of green plants, you’ll get lots of NIR radiation. [1]
7. Regular sunshine exposure not only increases your Vit D3 levels, but also your melatonin.

We all know by now that Vit D3 is critical for your health, not just for your bone health, but also for the overall health, including your immunity.  During this Covid-19 pandemic, there’s been much scientific research that shows low Vit D3 levels are highly correlated with the high infection and mortality rates of Coivd-19.  We have been asking you to get more sunshine in order to boost your immunity. Melatonin is one of the powerful antioxidants that we have been  promoting for the fight against Covid-19.

We all thought melatonin is produced at night in the pineal gland and when the sun is up and your eyes are exposed to the light, melatonin production stops.  New research begins to show that actually the melatonin produced in the pineal gland is only a very small portion of the total melatonin in your body, only 5% to be exact.  95% of melatonin is actually produced in your cells (in mitochondria, the powerhouse of your cells), under the near infrared (NIR) light in the sunshine. [2]

Melatonin (from the Pineal Gland):

• Melatonin protects against cancer via multiple pathways
  • WHO classifies circadian disruptive shift work as a probable carcinogen (Group 2A).
• Reduced cancer incidence in “totally” blind people (due to lack of melatonin production inhibition by light in these people). [3]

Melatonin has potent antioxidant activity

• Melatonin is produced within mitochondria in response to sunlight and provides targeted protection of mitochondria from free radicals.
• Mitochondria is protective against a range of diseases characterized by mitochondrial dysfunction, including cancers, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases and diabetes. Practically mitochondrial abnormality is found in most if not all chronic diseases where such research has been done.
• Melatonin may play a role in the prevention and treatment of Alzheimer’s and Parkinson’s diseases (oxidative stress appears to be a key mechanism) and even in Covid-19. [4]

References:

1. Twohig-Bennett C, Jones A. The health benefits of the great outdoors: A systematic review and meta-analysis of greenspace exposure and health outcomes. Environ Res. 2018 Oct;166:628-637. doi: 10.1016/j.envres.2018.06.030. Epub 2018 Jul 5. PMID: 29982151; PMCID: PMC6562165.
2. Zimmerman S. and Reiter, R. 2019. http://www.melatonin-research.net/index.php/MR/article/view/19
3. Feychting M, Osterlund B, Ahlbom A. Reduced cancer incidence among the blind. Epidemiology. 1998 Sep;9(5):490-4. PMID: 9730026.
4. Reiter RJ, Ma Q, Sharma R. Melatonin in Mitochondria: Mitigating Clear and Present Dangers. Physiology (Bethesda). 2020 Mar 1;35(2):86-95. doi: 10.1152/physiol.00034.2019. PMID: 32024428.
5. https://www.youtube.com/watch?v=5YV_iKnzDRg&t=4530s

Debate on diet is abundant, whether it’s low carb, low fat or high protein. But there is little doubt in the medical literature that caloric restriction offers abundant health benefits.

I am just finishing a 48 hours fasting, as I am writing this article.

A group of scientists from Yale University and the Pennington Biomedical Research Center recently reported on Science in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) clinical trial showed that a 14% calorie intake reduction improves health with improved metabolic and immune responses, over a period of 2 years.

We have been advising our patients/clients to go on healthy diet including caloric restriction (via intermittent fasting) and low carb/ketogenic diet, nutritional supplementation for weight loss, metabolic disease management for decades with excellent results. We have helped tens of thousands of patients to successfully lose weight. We have improved or cured diabetes, high cholesterol, coronary heart disease, autoimmune diseases, chronic fatigue syndrome and even cancer.

You can achieve caloric restriction via intermittent fasting.  I often start a patient acute acute inflammatory state esp. those with autoimmune diseases.

The following is from a woman in her 70s with acute inflammatory skin rash. In addition to high dose Vit C and TotoCell Nutrition, I also placed on caloric restriction, low carb/ketogenic diet. She fasted for a week and saw significant reduction in inflammation. The following composite picture is her skin rash change in a month. She’s been having these red, itching rask for a long time. The one on the right is taken 1 month after treatment, showing significant improvement.

I also reported a local lady here in Columbia SC with skin rash, abdominal pain and fatigue. After being on dietary changes and nutritional supplements, she rapidly recovered.

I have been on intermittent fasting and low carbohydrate diet for ~10 years. I also follow a cyclic ketogenic diet. My stamina and health are in great shape. I compete on the badminton court 3-4 times a week, 2 hours each time against people 10-30 years younger than me. And yet many younger players seem to get tired more easily than I do. Of course, in addition to low carb/ketogenic diet, I also take nutritional supplements including high dose Vit C, TotoCell Nutrition (my own formula containing optimal doses of vitamins, antioxidants and nutrition boosting energy metabolism). I am on BioIdentical Hormone Replacement (BHRT) as well to promote my overall health and slow down the aging process.

Ref:

Spadaro O, Youm Y, Shchukina I, Ryu S, Sidorov S, Ravussin A, Nguyen K, Aladyeva E, Predeus AN, Smith SR, Ravussin E, Galban C, Artyomov MN, Dixit VD. Caloric restriction in humans reveals immunometabolic regulators of health span. Science. 2022 Feb 11;375(6581):671-677. doi: 10.1126/science.abg7292. Epub 2022 Feb 10. PMID: 35143297.

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 yeast^1,2, 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 laboratories^9,10. 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 training^16,17.

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).

Good news to older adults: It’s not too late to start exercise with a good nutrition program, you may be as young as young people in their 20s (with respect to muscle NAD+, energy metabolism).

Top science journal “Nature” recently (February 17, 2022) reported:

“Furthermore, we found that in the older adults, NAD+ muscle abundance positively correlated with muscle and mitochondrial health parameters. Taken together, these results show that NAD+ is lower in aging human muscle and that NAD+ abundance is directly associated with the healthy aging state of the individual.”

These researchers found that NAD+ is one of the most depleted metabolites with age, as it declines significantly with age. Among older adults who maintained exercise and good nutrition, their (60-85 years of age) NAD+ levels remained normal, even comparable to those of younger adults (in their 20s). This is very encouraging and interesting in the field of anti-aging medicine. This is yet another piece of evidence supporting the importance of mitochondrial energy metabolism in aging. Staying active with good nutrition, especially nutrients that support mitochondria and energy metabolism, is essential for anti-aging.

They also found that these metabolic changes that occur with aging can be reversed by exercise a nd nutrition. This is great for seniors: it’s not too late to start exercising and improve nutrition! Another important takeaway from this study is that glutathione is in high demand within cells as we age. Therefore, supplementing with glutathione or the nutrients used to produce glutathione is crucial. Unfortunately, ordinary glutathione is poorly absorbed orally, with the exception of liposomal glutathione, which is highly absorbed by the gastrointestinal tract. Glutathione precursors such as NAC are commonly used to increase intracellular glutathione levels.

Ref:

Janssens, GE, Grevendonk, L., Perez, RZ et al. Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nat Aging (2022). https://doi.org/10.1038/s43587-022-00174 -3