HEALTHY AGING
Healthy aging – why it’s a concern
The World Health Organization (WHO) reports that the aging population is growing faster than in the past. It is expected that by 2050, individuals 60 years and older will account for 22% of the world’s population (1). While in the United States, the U.S. Census Bureau reports that 21% of our population will be over 65 by 2030—outnumbering the population of children for the first time (2).
There is a strong connection between aging and age-related health conditions, commonly referred to as chronic health conditions. The top 10 chronic health conditions reported by the Centers for Disease Control and Prevention (CDC) include arthritis, cancer, chronic obstructive pulmonary disease, coronary heart disease, asthma, diabetes, hepatitis, hypertension, stroke, and weak/failing kidneys. In 2018, 51.8% of adults in the US had at least one of these conditions, with 27.2% experiencing multiple conditions (3).
Figure 1: Select chronic disease prevalence by age groups
Image credit: Aging and chronic disease - the American tsunami of bad health. Aging and Chronic Disease - The American Tsunami of Bad Health. https://www.prnewswire.com/news-releases/aging-and-chronic-disease--the-american-tsunami-of-bad-health-300939034.html. Published October 15, 2019. Accessed February 6, 2023.
What does it mean to “age healthy”
Aging is a biological process that results from molecular and cellular changes over time, not in a linear or consistent pattern, though it is associated to a person’s biological age. This process can result in health conditions that are often associated with aging, as mentioned above. Genetics, physical and social environments, social interactions (personal and in the community), socioeconomic status, sex, ethnicity, use of tobacco, use of alcohol, dietary intake, physical activity, personal attitude, spirituality, and stress are all factors that can contribute to and can influence the healthy aging process, also sometimes referred to as ‘successful aging’ (1,4).
“Healthy aging is a continuous process of optimizing opportunities to maintain and improve physical and mental health, independence, and quality of life throughout the life course.” (5)
Aging, chronic diseases, and melatonin
While the depth of chronic diseases is beyond the scope of this article, there are key factors associated with aging and chronic disease that can be impacted by melatonin as depicted in Figures 2 and 3.
Figure 2: Factors involved in aging and chronic disease
Figure 3: Melatonin’s function in healthy aging
It begins in the mitochondria
The role of the mitochondria in healthy aging
Damage to the mitochondria can be related to various health concerns classified as mitochondrial disorders or mitochondrial dysfunction. It has been reported that “Mitochondrial dysfunction is one of the mechanisms related to diseases of aging.”(6). For example, neurodegenerative diseases (dementia, Alzheimer's disease, Parkinson’s disease, multiple sclerosis), chronic fatigue syndrome, diabetes, cardiovascular disease (hypertension), and psychiatric disorders are just some of the disorders related to mitochondrial dysfunction (7,8). Maintaining mitochondrial homeostasis is critical for overall health and healthy aging.
Melatonin’s role in the mitochondria
The mitochondria have a highly concentrated source of melatonin. Melatonin is found in almost all cells, tissues, and organs of the body, especially the mitochondria. In fact, “It has been hypothesized that mitochondria are a primary site of melatonin production…”(9).
Of note, it is speculated that about 5% of total melatonin is produced in the pineal gland, which is circulated through the body through serum and cerebrospinal fluid and can be taken up by the mitochondria, as needed (10,11). Whereas melatonin that is produced elsewhere in the body, including the mitochondria, is used by cells and referred to as a “non-releasable pool of melatonin.” (11) Two exceptions, include the gastrointestinal tract and skin, which may release melatonin produced based on conditional needs of the body (11).
Melatonin levels are the highest in teen years and decline with age, though it can be depleted with severe oxidative stress. Mitochondrial dysfunction and conditions place the body under severe oxidative stress (9). Antioxidants are often a key part of a nutritional intervention for mitochondrial dysfunction.
The mitochondria can induce the production of melatonin based on intracellular needs. Further, it has been reported that mitochondrial membranes can take up melatonin (from dietary or supplement sources), a function not shared by other antioxidants (6). Melatonin easily crosses the mitochondrial membrane (6). This feature may be one of the reasons melatonin is considered superior to other antioxidants. This process provides built-in protection against damage or cell death.
Melatonin levels in the mitochondria are higher than those found in the blood, likely due to the antioxidant requirements of the mitochondria (6).
Figure 5: Roles of melatonin in the mitochondria. Key: Continuous line indicates “stimulation”; dotted line indicates “inhibition”. (original Figure 2)
Image Credit: Martín Giménez VM, de Las Heras N, Ferder L, Lahera V, Reiter RJ, Manucha W. Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases. Diseases. 2021;9(2):30. Published 2021 Apr 14. doi:10.3390/diseases9020030. https://creativecommons.org/licenses/by/4.0/
Melatonin as an antioxidant
It has been speculated that melatonin is the oldest antioxidant in existence (12). As an antioxidant, melatonin is compared to vitamin antioxidants such as vitamins C and E, though it is distinctly different from these vitamins and other antioxidants.
It is useful to first understand that antioxidants are classified into three categories (13):
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Primary: These types prevent oxidant/free radical formation.
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Secondary: These types are scavengers of free radicals or clean up the reactive molecules.
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Tertiary: These types repair oxidized molecules damaged from free radical activity.
Melatonin fits into all three of these categories as described below.
First, unlike vitamin antioxidants, which are obtained solely from the diet or in supplement form, melatonin can be obtained in the diet or as a supplement and is produced within the body (9).
Second, it is more potent than other antioxidants. A single melatonin molecule is reported to scavenge up to 10 reactive oxygen and nitrogen species – a secondary antioxidant activity (14,15). In comparison, vitamin C, only scavenges 1-2 free radicals (11).
What is novel is that even the metabolites of melatonin can be used to scavenge free radicals, including those that initially form (primary metabolites), followed by the cascade of metabolites to the secondary, tertiary, and even quaternary levels (14,15).
This feature is quite the exception for an antioxidant, considering that in some cases, antioxidants under certain conditions can become pro-oxidants. For example, when vitamin C reacts with copper, it can become a free radical or pro-oxidant. Interestingly, melatonin reduced the pro-oxidant effects of vitamin C (16).
A study comparing synthetic melatonin to phytomelatonin (plant-based) found phytomelatonin to be 267-470% more potent at scavenging free radicals. Additionally, it was 100% more efficient at reducing cellular reactive oxygen species (17).
When too many free radicals build up, it can result in chronic inflammation, cell, and DNA damage,
speed up aging, and promote disease.
Third, melatonin has a dual nature. It can reside in water and fat. Most antioxidants are usually only either water-soluble or fat-soluble, but not both. As a result, melatonin can travel to many parts of the body, including the blood, mostly water, and the brain, mostly fat. This unique feature of melatonin also makes it readily available for use in the mitochondria of the cell, which have an outer and inner cellular membrane through which melatonin can easily cross. It is here, in the mitochondria, that melatonin aids in reducing free radicals.
Finally, melatonin doesn't just work as the line of defense against free radicals. It is also able to:
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Change gene expression in the cell to increase endogenous production of melatonin (15).
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Suppress gene activity involved in the generation of free radicals (15).
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Upregulate antioxidant defense enzymes (SOD, catalase, glutathione peroxidase)- a primary antioxidant activity (14).
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Promote DNA repair after damage – a tertiary antioxidant activity (12).
Melatonin protects the mitochondria from ROS.
Melatonin can protect mitochondria from ROS damage in two ways: (18)
1) by preventing the formation of ROS precursors
2) by scavenging ROS as soon as they are produced
By avoiding damage caused by ROS, mitochondria can increase the production of energy (ATP) (8). Maintaining ATP production protects the mitochondrial membrane from collapsing, prevents an influx of calcium, inhibits membrane permeability, and reduces cell death (19). (An influx of calcium can damage cells.) Additionally, melatonin is unique as an antioxidant because it can promote DNA repair after damage (18).
Figure 6: Effects of melatonin and micronutrients on the mitochondria in the context of an oxidative stress/inflammatory disease. Key: dashed line indicates “inhibition”. (original Figure 3)
Image Credit: Martín Giménez VM, de Las Heras N, Ferder L, Lahera V, Reiter RJ, Manucha W. Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases. Diseases. 2021;9(2):30. Published 2021 Apr 14. doi:10.3390/diseases9020030. https://creativecommons.org/licenses/by/4.0/
Melatonin as an anti-inflammatory agent
A critical action of melatonin is an anti-inflammatory agent (Figure 6) throughout the body (20,21). Acute inflammation is beneficial as it protects us from injuries and infections. Chronic inflammation is problematic. This is at the core of chronic diseases and accelerates the aging process, often referred to as ‘inflamm-aging’. A more recent age-related term, ‘coagul-aging’, is used to describe hyperinflammatory states combined with coagulation disorders (22).
Melatonin works to help regulate pro-inflammatory states by mediating or inhibiting multiple proinflammatory molecules, such as cyclooxygenase (COX-2), and enhancing cell death in abnormal cells (21,23)Acting as an antioxidant, melatonin helps to decrease reactive oxygen species (ROS), which are inflammatory (15). Interestingly, a comparison of phytomelatonin with synthetic melatonin shows that plant melatonin is 646% more effective at blocking COX-2 than the synthetic format (17). In phytomelatonin supplements, additional compounds likely have an additive therapeutic effect. These active constituents include amino acids, fatty acids, vitamins, minerals, and phytonutrients such as beta-carotene, lutein, and chlorophyll (6).
As a result of melatonin’s anti-inflammatory action, melatonin is a possible therapy for many diseases that can be associated with inflamm-aging, including sleep disorders, cognitive and neurological concerns, cardiovascular health, gastrointestinal health, and cancer (6).
Summary
Healthy aging requires proper energy balance, mitochondrial health, free radical scavenging, antioxidant status, and anti-inflammatory activity. While one molecule cannot be expected to defer the aging process, melatonin is unique due to its intimate connection to the mitochondria and its antioxidant and anti-inflammatory capabilities
Author: Kim Ross, DCN
Reviewer: Deanna Minich, PhD
Last Updated: February 6, 2023
References
1. World Health Organization (WHO). Ageing and health [Internet]. World Health Organization. 2022 [cited 2022 Oct 12]. Available from: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
2. Vespa J. The U.S. Joins other Countries with Large Aging Populations [Internet]. Census.gov. 2019 [cited 2022 Oct 12]. Available from: https://www.census.gov/library/stories/2018/03/graying-america.html
3. Boersma P, Black LI, Ward BW. Prevalence of multiple chronic conditions among US adults, 2018. Prev Chronic Dis. 2020;17.
4. Healthy Aging [Internet]. U.S. Department of Health & Human Services. 2022 [cited 2023 Feb 1]. Available from: https://www.hhs.gov/aging/healthy-aging/index.html
5. Healthy Aging [Internet]. Pan American Health Organization/World Health Organization. [cited 2023 Feb 1]. Available from: https://www.paho.org/en/healthy-aging
6. Minich DM, Henning M, Darley C, Fahoum M, Schuler CB, Frame J. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients [Internet]. 2022;14(19). Available from: https://www.mdpi.com/2072-6643/14/19/3934/htm
7. Nelms, M, Sucher, K, Lacey K. Nutrition Therapy and Pathophysiology. 3rd ed. Boston: Cengage Learning; 2016.
8. Srinivasan V, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP. Melatonin in mitochondrial dysfunction and related disorders. International Journal of Alzheimer’s Disease. 2011.
9. Tan DX, Manchester LC, Esteban-Zubero E, Zhou Z, Reiter RJ. Melatonin as a potent and inducible endogenous antioxidant: Synthesis and metabolism. Molecules. 2015.
10. Reiter R, Sharma R, Rosales-Corral S, Manucha W, Chuffa LG de A, Zuccari DAP de C. Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells. Int J Mol Sci. 2021 Nov 19;22(22):12494.
11. Tan DX, Reiter RJ, Zimmerman S, Hardeland R. Melatonin: Both a Messenger of Darkness and a Participant in the Cellular Actions of Non-Visible Solar Radiation of Near Infrared Light. Biology (Basel). 2023 Jan 6;12(1):89.
12. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. Journal of Pineal Research. 2016.
13. Mehta SK, Gowder SJT. Members of Antioxidant Machinery and Their Functions. In: Basic Principles and Clinical Significance of Oxidative Stress. 2015.
14. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? Vol. 42, Journal of Pineal Research. 2007.
15. Hacışevki A, Baba B. An Overview of Melatonin as an Antioxidant Molecule: A Biochemical Approach. In: Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches. 2018.
16. Gitto E, Tan DX, Reiter RJ, Karbownik M, Manchester LC, Cuzzocrea S, et al. Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrrioxamine (desferoxamine) in rat liver homogenates. Journal of Pharmacy and Pharmacology. 2010;53(10).
17. Kukula-Koch W, Szwajgier D, Gaweł-Bęben K, Strzępek-Gomółka M, Głowniak K, Meissner HO. Is phytomelatonin complex better than synthetic melatonin? The assessment of the antiradical and anti-inflammatory properties. Molecules. 2021;
18. Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Zhou XJ, Xu B. Mitochondria: Central organelles for melatonins antioxidant and anti-Aging actions. Molecules. 2018.
19. Kopustinskiene DM, Bernatoniene J. Molecular mechanisms of melatonin-mediated cell protection and signaling in health and disease. Pharmaceutics. 2021.
20. Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2022;0123456789.
21. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation. Vol. 2017, International Journal of Endocrinology. 2017.
22. Xu K, Wei Y, Giunta S, Zhou M, Xia S. Do inflammaging and coagul-aging play a role as conditions contributing to the co-occurrence of the severe hyper-inflammatory state and deadly coagulopathy during COVID-19 in older people? Vol. 151, Experimental Gerontology. 2021.
23. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, et al. Melatonin’s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules. 2020;10(9).