Reply to Pluta, R. Comment on “Minich et al. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients 2022, 14, 3934”

We would like to thank Dr. Pluta for his thoughtful comments [1] on our review article [2] questioning whether melatonin is the “next vitamin D”. Specifically, Dr. Pluta detailed several aspects of melatonin’s functions in brain health and in neurodegenerative processes related to Alzheimer’s disease. From the research he presented, towards the end of these comments, he summarized: “All these studies suggest that melatonin may be effective in preventing the pathology of amyloid and tau protein and modulating the metabolism of the amyloid protein precursor. I have doubts about the suggestion that melatonin is “next vitamin D” [sic]. Does vitamin D have the therapeutic properties described above for melatonin?”

As we stated in our article, there are several similarities between melatonin and vitamin D: “Both act as hormones, affect multiple systems through their immune-modulating, anti-inflammatory functions, are found in the skin, and are responsive to sunlight and darkness. In fact, there may be similarities between the widespread concern about vitamin D deficiency as a “sunlight deficiency” and reduced melatonin secretion as a result of “darkness deficiency” from overexposure to artificial blue light”. In other words, the two have overlapping functions and complementary activities related to light exposure. Additionally, both compounds decline endogenously with age [3,4]. They are associated with increases in age-associated conditions such as cancer [5,6], cognitive impairment/dementia [7,8,9], autoimmune diseases [10,11,12], and even cardiovascular disease [13,14], thereby indicating that there may be an increased need state throughout the lifespan. Thus, we suggested that melatonin may even be a necessary “nutrient”, similar to vitamin D.

Our suggestion is not that one replaces the other, but that there may be some similarities in function. Furthermore, our intention in this review article was to provide a survey of multiple areas of clinical concern related to how melatonin and vitamin D may be involved in foundational mechanisms associated with a broad spectrum of disease pathologies, including their (1) anti-inflammatory activities [15]; (2) antioxidant potential [16]; and (3) mitochondrial regulation [17].

What Dr. Pluta seems to be asking is how vitamin D compares with melatonin in relation to amyloid and tau protein pathology. In his comment, he cited several studies indicating melatonin’s proficiency in accomplishing many functions related to amyloid metabolism and inhibiting the tau protein’s hyperphosphorylation. While these are important hallmarks of dementia, we would like to offer a fundamental mechanistic view of neurodegenerative diseases involving the three aforementioned mechanisms.

Specifically, copious research has suggested that inflammation is part of the underlying dysfunction that can ultimately result in or exacerbate the dysregulation, aggregation, and lack of proper elimination of amyloid and tau proteins [18,19]. Moreover, oxidative stress in the brain has been associated with dementia [20,21,22,23], most likely due to the lipid-rich nature of the brain matter. As stated in our review paper, vitamin D and melatonin are fat-soluble antioxidants that can cross the blood–brain barrier. Finally, mitochondrial function is one of the lynchpins of healthy metabolism and neurological function. With damage to the mitochondria through free radical activity or inflammation, there will be impairments in energy production, which could have significant implications for brain health [24]. Mitochondrial dysfunction is becoming increasingly recognized as part of the more extensive pathology underlying neurodegeneration [25] and Alzheimer’s disease [26,27,28,29].

Separate from the established and emerging research aiming to support the shared mechanisms of vitamin D and melatonin in brain- and neurological-related disorders, there is some indication that vitamin D may play a role in amyloid [30,31,32,33,34] and tau protein [35,36,37] metabolism, which are the distinct areas that Dr. Pluta showed particular interest in, and concern about, regarding our provocative statement of query as to whether melatonin is the “next vitamin D”.

In conclusion, we are grateful to Dr. Pluta for raising the question about the similarities between vitamin D and melatonin and whether the two may be seen as having identical functions, particularly for brain and neurological health. To reiterate, while we would not want to suggest that the two are interchangeable, we documented that they could target common mechanistic pathways underlying the pathologies of several chronic diseases and even foster healthy brain aging.

Author Contributions

Conceptualization, D.M.M.; writing—original draft preparation, D.M.M.; writing—review and editing, M.H., C.D., M.F., C.B.S. and J.F. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

All authors are independent contractors of, or have a commercial interest in Symphony Natural Health, a commercial entity that sells melatonin in the retail and health professional channels.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

References

1. Pluta, R. Comment on Minich et al. Is melatonin the “Next Vitamin D”?: A review of emerging science, clinical uses, safety, and dietary supplements. Nutrients 2022, 14, 3934. Nutrients; 2023; 15, 1506. [DOI: https://dx.doi.org/10.3390/nu15061506]

2. Minich, D.M.; Henning, M.; Darley, C.; Fahoum, M.; Schuler, C.B.; Frame, J. Is melatonin the “Next Vitamin D”?: A review of emerging science, clinical uses, safety, and dietary supplements. Nutrients; 2022; 14, 3934. [DOI: https://dx.doi.org/10.3390/nu14193934] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36235587]

3. Gallagher, J.C. Vitamin D and Aging. Endocrinol. Metab. Clin. N. Am.; 2013; 42, pp. 319-332. [DOI: https://dx.doi.org/10.1016/j.ecl.2013.02.004]

4. Grivas, T.B.; Savvidou, O.D. Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis. Scoliosis; 2007; 2, pp. 6-14. [DOI: https://dx.doi.org/10.1186/1748-7161-2-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17408483]

5. Lawler, T.; Andersen, S.W. Serum 25-Hydroxyvitamin D and Cancer Risk: A Systematic Review of Mendelian Randomization Studies. Nutrients; 2023; 15, 422. [DOI: https://dx.doi.org/10.3390/nu15020422]

6. Ahmad, S.B.; Ali, A.; Bilal, M.; Rashid, S.M.; Wani, A.B.; Bhat, R.R.; Rehman, M.U. Melatonin and Health: Insights of Melatonin Action, Biological Functions, and Associated Disorders. Cell. Mol. Neurobiol.; 2023; pp. 1-22. [DOI: https://dx.doi.org/10.1007/s10571-023-01324-w]

7. Annweiler, C.; Llewellyn, D.J.; Beauchet, O. Low Serum Vitamin D Concentrations in Alzheimer’s Disease: A Systematic Review and Meta-Analysis. J. Alzheimers Dis.; 2013; 33, pp. 659-674. [DOI: https://dx.doi.org/10.3233/JAD-2012-121432]

8. Chakkera, M.; Ravi, N.; Ramaraju, R.; Vats, A.; Nair, A.R.; Bandhu, A.K.; Koirala, D.; Pallapothu, M.R.; Mariñez, M.G.Q.; Khan, S. The Efficacy of Vitamin D Supplementation in Patients with Alzheimer’s Disease in Preventing Cognitive Decline: A Systematic Review. Cureus; 2022; 14, e31710. [DOI: https://dx.doi.org/10.7759/cureus.31710]

9. Prodhan, A.S.U.; Cavestro, C.; Kamal, M.A.; Islam, M.A. Melatonin and Sleep Disturbances in Alzheimer’s Disease. CNS Neurol. Disord.-Drug Targets; 2021; 20, pp. 736-754. [DOI: https://dx.doi.org/10.2174/1871527320666210804155617]

10. Dipasquale, V.; Presti, G.L.; Milani, G.P.; Corsello, A.; Agostoni, C.; Romano, C. Vitamin D in Prevention of Autoimmune Diseases. Front. Biosci.; 2022; 27, 288. [DOI: https://dx.doi.org/10.31083/j.fbl2710288]

11. Muñoz-Jurado, A.; Escribano, B.M.; Caballero-Villarraso, J.; Galván, A.; Agüera, E.; Santamaría, A.; Túnez, I. Melatonin and multiple sclerosis: Antioxidant, anti-inflammatory and immunomodulator mechanism of action. Inflammopharmacology; 2022; 30, pp. 1569-1596. [DOI: https://dx.doi.org/10.1007/s10787-022-01011-0] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35665873]

12. Bondy, S.C. Melatonin and Regulation of Immune Function: Impact on Numerous Diseases. Curr. Aging Sci.; 2020; 13, pp. 92-101. [DOI: https://dx.doi.org/10.2174/1874609813666200711153223] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32651969]

13. Pál, É.; Ungvári, Z.; Benyó, Z.; Várbíró, S. Role of Vitamin D Deficiency in the Pathogenesis of Cardiovascular and Cerebrovascular Diseases. Nutrients; 2023; 15, 334. [DOI: https://dx.doi.org/10.3390/nu15020334]

14. Tobeiha, M.; Jafari, A.; Fadaei, S.; Mirazimi, S.M.A.; Dashti, F.; Amiri, A.; Khan, H.; Asemi, Z.; Reiter, R.J.; Hamblin, M.R. et al. Evidence for the Benefits of Melatonin in Cardiovascular Disease. Front. Cardiovasc. Med.; 2022; 9, 888319. [DOI: https://dx.doi.org/10.3389/fcvm.2022.888319]

15. Murdaca, G.; Gangemi, S. Vitamin D in Health and Disease. Biomedicines; 2022; 11, 10. [DOI: https://dx.doi.org/10.3390/biomedicines11010010]

16. Miao, D.; Goltzman, D. Mechanisms of action of vitamin D in delaying aging and preventing disease by inhibiting oxidative stress. Vitam Horm.; 2023; 121, pp. 293-318. [DOI: https://dx.doi.org/10.1016/bs.vh.2022.09.004]

17. Żmijewski, M.A. Nongenomic Activities of Vitamin D. Nutrients; 2022; 14, 5104. [DOI: https://dx.doi.org/10.3390/nu14235104]

18. Bowirrat, A. Immunosenescence and Aging: Neuroinflammation Is a Prominent Feature of Alzheimer’s Disease and Is a Likely Contributor to Neurodegenerative Disease Pathogenesis. J. Pers. Med.; 2022; 12, 1817. [DOI: https://dx.doi.org/10.3390/jpm12111817]

19. Stephenson, J.; Nutma, E.; Van Der Valk, P.; Amor, S. Inflammation in CNS neurodegenerative diseases. Immunology; 2018; 154, pp. 204-219. [DOI: https://dx.doi.org/10.1111/imm.12922]

20. Maynard, S.; Fang, E.F.; Scheibye-Knudsen, M.; Croteau, D.L.; Bohr, V.A. DNA Damage, DNA Repair, Aging, and Neurodegeneration. Cold Spring Harb. Perspect. Med.; 2015; 5, a025130. [DOI: https://dx.doi.org/10.1101/cshperspect.a025130]

21. Tobore, T.O. On the central role of mitochondria dysfunction and oxidative stress in Alzheimer’s disease. Neurol. Sci.; 2019; 40, pp. 1527-1540. [DOI: https://dx.doi.org/10.1007/s10072-019-03863-x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30982132]

22. Islam, B.U.; Jabir, N.R.; Tabrez, S. The role of mitochondrial defects and oxidative stress in Alzheimer’s disease. J. Drug Target.; 2019; 27, pp. 932-942. [DOI: https://dx.doi.org/10.1080/1061186x.2019.1584808] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30775938]

23. Zhao, J.; Huai, J. Role of primary aging hallmarks in Alzheimer’s disease. Theranostics; 2023; 13, pp. 197-230. [DOI: https://dx.doi.org/10.7150/thno.79535]

24. Novack, G.V.; Galeano, P.; Castaño, E.M.; Morelli, L. Mitochondrial Supercomplexes: Physiological Organization and Dysregulation in Age-Related Neurodegenerative Disorders. Front. Endocrinol.; 2020; 11, 600. [DOI: https://dx.doi.org/10.3389/fendo.2020.00600]

25. Grimm, A.; Eckert, A. Brain aging and neurodegeneration: From a mitochondrial point of view. J. Neurochem.; 2017; 143, pp. 418-431. [DOI: https://dx.doi.org/10.1111/jnc.14037]

26. Adiele, R.C.; Adiele, C.A. Mitochondrial Regulatory Pathways in the Pathogenesis of Alzheimer’s Disease. J. Alzheimers Dis.; 2016; 53, pp. 1257-1270. [DOI: https://dx.doi.org/10.3233/jad-150967]

27. Mahley, R.W. Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer’s disease. Curr. Opin. Neurobiol.; 2023; 79, 102684. [DOI: https://dx.doi.org/10.1016/j.conb.2023.102684]

28. Pires, M.; Rego, A.C. Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies. Int. J. Mol. Sci.; 2023; 24, 778. [DOI: https://dx.doi.org/10.3390/ijms24010778]

29. Oliver, D.M.; Reddy, P.H. Molecular Basis of Alzheimer’s Disease: Focus on Mitochondria. J. Alzheimers Dis.; 2019; 72, pp. S95-S116. [DOI: https://dx.doi.org/10.3233/jad-190048]

30. Patel, P.; Shah, J. Vitamin D3 supplementation ameliorates cognitive impairment and alters neurodegenerative and inflammatory markers in scopolamine induced rat model. Metab. Brain Dis.; 2022; 37, pp. 2653-2667. [DOI: https://dx.doi.org/10.1007/s11011-022-01086-2]

31. Kang, J.; Park, M.; Lee, E.; Jung, J.; Kim, T. The Role of Vitamin D in Alzheimer’s Disease: A Transcriptional Regulator of Amyloidopathy and Gliopathy. Biomedicines; 2022; 10, 1824. [DOI: https://dx.doi.org/10.3390/biomedicines10081824]

32. Peng, H.B.; Bukuroshi, P.; Durk, M.R.; Grootendorst, P.; Yan, X.; Pan, S.R.; Lannoy, I.A.M.; Pang, K.S. Impact of age, hypercholesterolemia, and the vitamin D receptor on brain endogenous β-amyloid peptide accumulation in mice. Biopharm. Drug Dispos.; 2021; 42, pp. 372-388. [DOI: https://dx.doi.org/10.1002/bdd.2297]

33. Bivona, G.; Lo Sasso, B.; Gambino, C.M.; Giglio, R.V.; Scazzone, C.; Agnello, L.; Ciaccio, M. The Role of Vitamin D as a Biomarker in Alzheimer’s Disease. Brain Sci.; 2021; 11, 334. [DOI: https://dx.doi.org/10.3390/brainsci11030334]

34. Jia, J.; Hu, J.; Huo, X.; Miao, R.; Zhang, Y.; Ma, F. Effects of vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer’s disease: A randomised, double-blind, placebo-controlled trial. J. Neurol. Neurosurg. Psychiatry; 2019; 90, pp. 1347-1352. [DOI: https://dx.doi.org/10.1136/jnnp-2018-320199] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31296588]

35. Wu, T.-Y.; Zhao, L.-X.; Zhang, Y.-H.; Fan, Y.-G. Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice. Neurochem. Int.; 2022; 153, 105260. [DOI: https://dx.doi.org/10.1016/j.neuint.2021.105260] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34953963]

36. Scrimgeour, A.G.; Condlin, M.L.; Loban, A.; DeMar, J.C. Omega-3 Fatty Acids and Vitamin D Decrease Plasma T-Tau, GFAP, and UCH-L1 in Experimental Traumatic Brain Injury. Front. Nutr.; 2021; 8, 685220. [DOI: https://dx.doi.org/10.3389/fnut.2021.685220]

37. Lin, C.-I.; Chang, Y.-C.; Kao, N.-J.; Lee, W.-J.; Cross, T.-W.; Lin, S.-H. 1,25(OH)2D3 Alleviates Aβ(25-35)-Induced Tau Hyperphosphorylation, Excessive Reactive Oxygen Species, and Apoptosis Through Interplay with Glial Cell Line-Derived Neurotrophic Factor Signaling in SH-SY5Y Cells. Int. J. Mol. Sci.; 2020; 21, 4215. [DOI: https://dx.doi.org/10.3390/ijms21124215] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32545801]