Essay 5: Melatonin

A likely candidate supplement for significant health span extension

In March, 2023, a comment below in the Gerontology Research Group stimulated my interest in melatonin.  I have included below substantial references and notes taken from scientific literature.  Here is a summary of my hypotheses which you are invited to discuss with your physician.

• Melatonin is safe when taken as a supplement, even at high levels in the 40-100mg range.
• Melatonin is a powerful antioxidant which affects other beneficial genes are molecules which prolong healthspan such as Nrf2 and Sirtuins, benefiting the heart, liver, brain, and other organs, reducing likelihood of diseases in all of these sites.
• Oral melatonin has a half-life of 4 to 6 hours, so most is excreted over 5 hours.
• While I have been taking 3-5 mg four times a week, I intend to increase my dosage now to 10mg six times a week.
• With further research expected in the coming decade, dosages of up to 100 mg may be justified.

BACKGROUND TO SUMMARY ABOVE:
GRG wrote:

Is there a consensus dosage for Melatonin for anti-aging purposes? What are folks points of view and experiences? For those with opinions, did you gain palpable immediate benefits of any kind? Thanks in advance!

Sorry this reply is so long.  First is my dosage and experience.  But then is an outstanding 2022 review that recommends 40-100mg nightly, though there is not enough research on this.

I have always used between 3 and 10mg, depending on cost.  The AGE study where changes in gene  expression were reported was not published, but I believe only used a low dosage, perhaps 10mg per nite. I have taken melatonin 4 nites a week since around 1990.  I only take it that often because I do not want to disrupt my biological clock that produces melatonin naturally to put me to sleep.  The supplemental dosage does make me sleepy very rapidly.

 

Reference (2022) Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases

1) a 10-fold decrease in pineal melatonin production in octogenarians compared to teenagers was observed, which results in a significant attenuation of the antioxidant, anti-inflammatory, and mitochondrial optimizing effects of melatonin (Melhuish Beaupre et al., 2021)

2)melatonin has even been proposed as a molecule potentially capable of extending lifespan by allowing healthy aging (Karadas et al., 2019).

3) melatonin may also upregulate Nrf2, an anti-aging gene.

4)DOSAGE:  it has been demonstrated that daily bedtime administration of 3–12 mg of melatonin is effective in the treatment of sleep behavior disorders and may stop or slow neurodegeneration associated with these diseases. However, if doses of melatonin that have been effective in animal models to reduce not only sleep disorders but also the symptomatology of PD are projected to humans, these would be in the range of 40–100 mg/day, a dose that is consistent with studies in which melatonin was used to inhibit COVID-19 infections (Reiter et al., 2022). Clearly, clinical studies using this dose range are urgently needed to provide information on the optimal dose of melatonin for human use in relation to the treatment of symptomatology of this and other neurodegenerative diseases (Cardinali, 2019; Pérez-Lloret and Cardinali, 2021).

5) The dose issue is generally considered to not be a major problem when melatonin is used because of its uncommonly low toxicity and its safety over a very large dose range.

6) Looking across the entire life span, nocturnal serum melatonin levels appear low during the first 6 months of life, then they peak at 1–3 years of age. By 15–20 years old individuals already experience, on average, an 80% decline in melatonin levels and this decline continues into old age (70–90 years)⁹⁵.

7) Using saliva samples that were collected over a 24-h period, they noticed that the median nocturnal melatonin response at 4 a.m. was significantly lower in the cognitively impaired group. However, there were no significant differences at any other time point¹¹⁷. The question then becomes: would exogenous melatonin be of benefit? Although the question cannot be answered directly, we do have some insight from animal models. For example, mice exposed to formaldehyde suffer from cognitive impairments and experience an increase in oxidative stress, as noted by higher levels of ROS, 50% reduction in GSH, and decreased endogenous melatonin. However, melatonin treatment was able to ameliorate the reduction in GSH, restore melatonin levels and improve cognitive functioning¹¹⁸. Taken together, this evidence supports a decline in melatonin and an increase in oxidative stress during cognitive decline, independent of age.

8) Prior to three months of age there is little melatonin (MLT) secretion in humans. MLT production then commences, becomes circadian, and reaches its highest nocturnal blood levels between the ages of one to three years. During the remainder of childhood, nocturnal peak levels drop progressively by 80%. In adults, these levels show an additional drop of some 10%, mainly during senescence. The large drop in serum MLT during childhood is probably the result of the increase in size of the human body, despite a constant MLT production after infancy. The additional decline of MLT with higher age may be due to a yet unidentified physiological mechanism accompanying senescence.

9) Melatonin might be used in the prevention of aging. (1998)

10) Since melatonin and SIRT3 have cohabitated in the mitochondria for many eons, we predict that these molecules interact in many other ways to control mitochondrial physiology. It is predicted that these mutual functions will be intensely investigated in the next decade and importantly, we assume that the findings will have significant applications for preventing/delaying some age-related diseases and aging itself.(2018) Sirtuins are NAD+-dependent deacetylates which account for post-translational modifications of molecules within cells; sirtuins have a wide variety of functions including the promotion of longevity and the prevention in age-related diseases.

11) The observations of Venegas et al. [177] do not preclude the possibility that mitochondria may both avidly take up melatonin from extracellular locations, e.g., blood, as well as synthesize it. As shown above, the reports of Jou et al. [167,168] document that when cultured cells are incubated with melatonin, it may rapidly gain access to mitochondria where it visually lowers free radical products.