Here are a few thought-stimulating papers in this issue by Skutsch et al. They noted that COVID-19 deaths per million were higher in South America than in either EU & North America, Asia, Africa, & Oceania had death rates only a 1/5 of those in South America. This data came out in Vol 5 No 3 (2022): Melatonin Research. Since the world just went through COVID I thought I’d use this publication to show you how important the creation and maintenance of the production of melatonin is in your mitochondria. Many people are unaware that most melatonin in mammals is not made in the pituitary gland. It is actually made in your mitochondria under the control of UV/IR-A light.
In 1958, an America Dermatologist was doing research removing cow pineal glands to see how melatonin levels would change. Obviously, there should be no melatonin left anywhere in the body if we believed in conventional wisdom.
Yet, the dermatologist found melatonin was still present in the blood! (Cite 6)
Mitochondrial melatonin (cite 15-17 below) also controls mitochondrial autophagy and apoptosis. This means mitochondrial biology self-regulates itself using AM sunlight to regenerate every photoreceptor in your body.
Mother Nature put melatonin EVERYWHERE in our bodies where mitochondria are located.
Melatonin is made in your:
Eye (lens, retina, ciliary body, Inner ear)
Thymus
Immune cells (T cells have the highest concentration of any cell)
Gut (there is 400 times more melatonin in your gut than your pineal gland)
Microbiome
Ovaries and testes
Whatever organ you can name with mitochondria, melatonin has been found to be made there without the pineal gland present.
Getting back to the COVID story you can begin to see why so many people with low Vitamin D states and diseases that have low vitamin D levels would get this disease. It also highlights why telling people to stay inside was a public health failure.
They found that the COVID-19 death rate was strongly associated with overweight & HIGH latitudes but not with the vaccine coverage percentage in these countries = lack of sun was a big deal because these people had too little melatonin production.
In an attempt to explain differences, they hypothesized: (1) In overweight people there is less penetration of near-infrared radiation (NIR) to the depth of important organs; stimulation of these organs by NIR would result in elevated production of mitochondrial melatonin. In overweight people, fatty tissue holds much of the body´s 25(OH)Vitamin D3 leaving less circulating in the blood making it less systemically protective. The hypothesis advanced by Skutsch et al. receives support from an article by Zimmerman and Reiter published also in the issue I mentioned above.
They observed large quantities of melatonin, greater than 5 pg/ml min ramp rates for plasma and sweat melatonin, have been detected during strenuous exercise in sunlight as compared to 0.15 pg/ml min ramp rates for plasma melatonin under dim light melatonin onset conditions.
This difference is in excess of 30-fold! Sunlight contains high levels of NIR which likely stimulate mitochondrial melatonin production to help T-regulator cells fight disease. High-latitude terrestrial light generally has less NIR irradiation and excessive weight restricts NIR penetration to important organs such as the lungs and heart involved in COVID.
Thus, both obesity and high latitude are factors that limit local melatonin production and compromise the protective effects of locally-produced melatonin in these important organs. This is why we saw people with obesity and co-morbidities die from this disease. Almost no one died from COVID unless they had co-morbidities. These observations not only apply to C-19 patients but to other disorders including diabetes, neurodegenerative diseases, and seasonal depression.
This new data implies that if you have better mitochondria, then you make more melatonin! Not only do you stave off pretty much every disease known to man, you also get better sleep! This also explains how people with conventionally defined mitochondrial diseases have poor sleep (cite 18). This would imply that “high heteroplasmy rates” (see above: many poorly functioning mitochondria = disease) lead to poor sleep. So, if you do things for your mitochondria you’re doing big things for sleep! This is why poor sleep is a proxy for mitochondrial damage.
Another implication of this relationship between melatonin as an antioxidant is that being under oxidative stress would enhance melatonin production. The most important example is ultraviolet (UV) light which triggers the eventual production of melatonin by triggering anti-oxidant defense mechanisms (cite 19).
This brings us to a secondary role of melatonin, it is the conductor of the circadian rhythm trained by UV light in the eye. Melatonin not only resets your oxidation status in the central retinal pathways in front of the SCN and our habenular nucleus, but it also resets the “clocks” throughout your body. Long story short, it acts on genes and proteins involved in your molecular circadian clocks (cite 20). Melatonin production in your mitochondria is controlled by the original clock: the SUN!
UV/IR-A light in your eye determines your circadian rhythm in your SCN and your moods due to the connections in the habenular nucleus link to your production of melatonin in both of these brain regions connected to your eye!!!
Look at the biochem chart below:
Melatonin production starts with the amino acid tryptophan. The more light energy absorbed from the sun tryptophan has, the faster it can make it to melatonin.
UV light gives tryptophan more energy (cite 21)
UV light also sets the “rhythm” to produce melatonin via neuropsin (OPN5) (cite 22).
In the short term, this leads to more serotonin available (tryptophan goes to serotonin before melatonin) (cite 23). In fact, natural light exposure in someone’s eye increases serotonin by itself likely for this mechanism.
Altogether, these set the stage for your “nighttime melatonin casserole” in your brain.
UV light in your eye helps you make a bunch of serotonin (the ingredients) and set the circadian rhythm (set the temperature and time in the oven). The result is that at nighttime, your melatonin-making enzymes in your pineal gland turn on and this allows for the massive conversion of serotonin to melatonin!
Hence, melatonin is “made” in your eye in the morning via UV/IR-A light.
That’s why you must get UV light on your eyeballs every single day to make the most melatonin possible. This is why I tell people to act like the Sphinx at sunrise. Face the east and look toward the sun while grounding your limbs allows you to absorb a ton of light energy to activate tryptophan.
It’s simple when you see all the basics laid out.
Go outside between 7 AM and Noon (if you want to be fancy, UV light is available as soon as the UV index = 1)
Exposure your naked eye to unfiltered sunlight (no glasses, contacts, windows, cats, etc.)
Get at least 3-5 minutes, but more is better to activate tryptophan. Below is how light activates it. Note the amount of rings melatonin has compared to leptin!
SUMMARY
Mitochondriacs need to step up their game on their understanding of what melatonin is, does, and how we use it. This hormone controlled most other hormones in eukaryotes before leptin evolved. Its function changed once leptin showed up after the Cambrian explosion.
It is a hormone much like testosterone and cortisol. This means that melatonin is made and then has actions elsewhere but also locally in tissues.
It is both soluble in fat and water. That means that melatonin will go through cell membranes (which have a lot of fat) and then into your blood (which is mainly water = 93%). The implication of this is that as soon as melatonin is made is going to travel elsewhere in your body where it is needed.
It is not sticking around where it was made UNLESS it is being used up locally by tissues under oxidative stress.
First and foremost, melatonin is an anti-oxidant. Long ago during the Sun’s midlife crisis, its light increased in strength by releasing 10% more UV light, and subsequently, this fueled the creation of more oxygen on planet Earth. This changed Earth’s surface from a relatively “harsh” primordial soup to an updated environment. Just a change in light changed things. Life adapted, by adding leptin biology to the melatonin story you see here in this blog. With a stronger sun, living things were getting more oxidized by oxygen and UV light. Life had to come up with a kick-butt anti-oxidant to offset this new environment. As evolution would have it, melatonin was made to do the job. (cite 1)
Melatonin is the “Old Zeus” of endogenous anti-oxidants. Leptin became the next generation of quantum upgrades. You can see all the rings it has compared to melatonin to deal with the change in sunlight. Melatonin and leptin together help ameliorate almost everything that’s oxidizing you. Oxidation = rust. Your mitochondria produce a ton of endogenous oxidants. taking exogenous antioxidants lowers endogenous production. We do not want that. Mitochondrial also produce superoxide, hydrogen peroxide, hydroxyl radical, nitric oxide, and peroxynitrite, free radicals. Luckily melatonin can control the “fire” caused by all these oxidants. (cite -2) And, melatonin is far more effective than vitamin C, Vitamin A, Vitamin E, and glutathione as an anti-oxidant (cites 3-5). In part, the optimization of mitochondrial biology was so good that humans stopped making Vitamin C. When humans get really sick they can still derive benefits from IV Vitamin C but that is not how we want to treat people if we can avoid it.
There are some major implications for this science. You make the optimal amount of melatonin when you get good sleep and have a circadian rhythm that helps you produce your own melatonin. Thus, the best “anti-oxidant” you can take is 7-9 hours of AWESOME sleep. Not some supplement a centralized physician wants to sell you.
CITES
1- Tan DX, Hardeland R, Manchester LC, et al. The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection, and fitness. Biol Rev Camb Philos Soc. 2010;85(3):607-23.
2- Reiter RJ, Rosales-corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci. 2017;74(21):3863-3881.
3- Lopez-Burillo, S., Tan, D. X., Mayo, J. C., Sainz, R. M., Manchester, L. C., and Reiter, R. J. Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and alpha-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions. J Pineal Res 2003;34(4):269-277.
4- Montilla-Lopez P, Munoz-Agueda, MC, Lopez M, et al. Comparison of melatonin versus vitamin C on oxidative stress and antioxidant enzyme activity in Alzheimer’s disease induced by okadaic acid in neuroblastoma cells. Eur J Pharmacol. 9-20-2002;451(3):237-243.
5- Mayo JC, Tan DX, Sainz RM, Natarajan M, Lopez-Burillo S, Reiter RJ. Protection against oxidative protein damage induced by metal-catalyzed reaction or alkylperoxyl radicals: comparative effects of melatonin and other antioxidants. Biochimica et Biophysica Acta (BBA) – General Subjects. https://doi.org/10.1016/S0304-4165(02)00527-5….
6- Chowdhury I, Sengupta A, Maitra SK. Melatonin: fifty years of the scientific journey from the discovery of the bovine pineal gland to the delineation of functions in humans. Indian J Biochem Biophys. 2008;45(5):289-304.
7- Ostrin LA. Ocular and systemic melatonin and the influence of light exposure. Clin Exp Optom. 2019;102(2):99-108.
8- Fujimoto C, Yamasoba T. Oxidative stresses and mitochondrial dysfunction in age-related hearing loss. Oxid Med Cell Longev. 2014;2014:582849.
9- Ren W, Liu G, Chen S, et al. Melatonin signaling in T cells: Functions and applications. J Pineal Res. 2017;62(3)
10- Carrillo-vico A, Lardone PJ, Alvarez-sánchez N, Rodríguez-rodríguez A, Guerrero JM. Melatonin: buffering the immune system. Int J Mol Sci. 2013;14(4):8638-83.
11- Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol. 2011;17(34):3888-98.
12- Li Y, Hao Y, Fan F, Zhang B. The Role of Microbiome in Insomnia, Circadian Disturbance, and Depression. Front Psychiatry. 2018;9:669.
13- Tamura H, Takasaki A, Taketani T, et al. The role of melatonin as an antioxidant in the follicle. J Ovarian Res. 2012;5:5.
14- Acuña-castroviejo D, Escames G, Venegas C, et al. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014;71(16):2997-3025.
15- Kerenyi NA, Sotonyi P, Somogyi E (1975) Localizing acetylserotonin transferase by electron microscopy. Histochemistry 46:77–80 127.
16- Kerenyi NA, Balogh I, Somogyi E, Sotonyi P (1979) Cytochemical investigation of acetylserotonin-transferase activity in the pineal gland. Cell Mol Biol Incl Cyto Enzymol 25:259–262
17- Sakaguchi K, Itoh MT, Takahashi N, Tarumi W, Ishizuka B (2013) The rat oocyte synthesizes melatonin. Reprod Fertil Rev 25:674–682
18- Ramezani RJ, Stacpoole PW. Sleep disorders associated with primary mitochondrial diseases. J Clin Sleep Med. 2014;10(11):1233-9.
19- Kleszczyński K, Hardkop LH, Fischer TW. Differential effects of melatonin as a broad range UV-damage preventive dermato-endocrine regulator. Dermatoendocrinol. 2011;3(1):27-31.
20- Kandalepas PC, Mitchell JW, Gillette MU. Melatonin Signal Transduction Pathways Require E-Box-Mediated Transcription of Per1 and Per2 to Reset the SCN Clock at Dusk. PLoS ONE. 2016;11(6):e0157824.
21- Fraikin GY, Strakhovskaya MG, Ivanova EV, Rubin AB. Near-UV activation of enzymatic conversion of 5-hydroxytryptophan to serotonin. Photochem Photobiol. 1989;49(4):475-7.
22- Buhr ED, Yue WW, Ren X, et al. Neuropsin (OPN5)-mediated photoentrainment of local circadian oscillators in mammalian retina and cornea. Proc Natl Acad Sci USA. 2015;112(42):13093-8.
23- Miyamoto H, Nakamaru-ogiso E, Hamada K, Hensch TK. Serotonergic integration of circadian clock and ultradian sleep-wake cycles. J Neurosci. 2012;32(42):14794-803.
24- GW Lambert, C Reid, DM Kaye, GL Jennings, MD Esler, Effect of sunlight and season on serotonin turnover in the brain, The Lancet, Volume 360, Issue 9348, 2002, Pages 1840-1842, ISSN 01406736
sunlight) on your body surfaces. The lung is one of the surfaces where topology and the topologic charge are massively important in the control of hydrogen flow in her body especially in mitochondria. At night, her body may not even realize it’s night due to lack of connection to the earth and artificial lights, because NO ONE at UCLA even knew that melanopsin was present in the eye, skin/fat to cause chronic inflammatory damage. In fact, the skin damage she got from the blue light likely made her lungs worse daily. Why? All opsin are loosely bound to Vitamin A and as Vitamin A drops it causes circadian mismatches at all surfaces because melatonin levels drop and this ruins cell membrane function which the lung relies upon.
