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SAN ANTONIO
MEDICINE

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(OXPHOS), which results in energy (ATP) production, free radicals are in delaying osteopenia/osteoporosis. Other pathological disorders
often produced in abundance especially in the mitochondria of diseased where melatonin has shown significant ameliorative effects include
cells with melatonin being at the ready to neutralize them. protection from ionizing and ultraviolet radiation, colitis, hearing loss
Since OXPHOS is unique to the inner mitochondrial membrane, and others. A check of PubMed with the appropriate search terms will
this organellar fragment is a major source of destructive free radicals. uncover many other disorders where melatonin has proven beneficial.
Thus, the high levels of melatonin in the mitochondrial matrix puts There may be no subdiscipline of medicine where melatonin does not
this antioxidant in a strategic position to scavenge the radicals before have some potential applications.
they mutilate a neighboring molecule. Despite the high efficacy of mel- With an excess of 3,000 publications on this subject, perhaps no
atonin and other antioxidants in doing their jobs, some free radicals disease has been more thoroughly tested relative to the favorable effects
invariably escape being neutralized and indiscriminately create molec- of melatonin than has been cancer, including from the perspectives of
ular havoc. Over the course of a lifetime, the accumulated oxidative prevention, therapy and quality of life of individuals with this disease.
stress erodes cells and renders them less capable of carrying out their This research has involved multiple cancer types with a notable empha-
respective functions, thereby contributing to signs of aging.9 sis on breast cancer. Likewise, multiple molecular mechanisms have
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Many serious ailments have a free radical component, including car- been examined in relation to the ability of melatonin to counteract
diovascular diseases, arthritis, cancer, chronic obstructive pulmonary dis- cancer initiation, proliferation and metastasis with the presumption
ease, skin deterioration, neurodegenerative diseases, viral and bacterial that its oncostatic actions are multifactorial. A well-documented Hall-
infections, autoimmune disorders, bone loss, inflammation and others. mark of Cancer is excessive free radical generation in mitochondria.
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Also, ultraviolet and ionizing radiation, toxin ingestion, legal and illegal Due to its highly efficient protection against free radicals, this may
drug ingestion, nicotine use and air pollutants promote OXPHOS inef- be one of many mechanisms by which melatonin modulates tumor
ficiency and generate massive numbers of free radicals. The ubiquity of metabolism and growth.
actions of melatonin stems from it being a highly efficient radical scav- Chemotherapeutic agents are major elements of the anti-cancer
enger which targets mitochondria, the home base for the production arsenal. A limitation to their use is their collateral toxicity, especially
of many toxic derivatives of oxygen. The molecular mutilation resulting when it involves critical organs such as the heart. Melatonin has been
from oxidative stress is a common denominator for many diseases. examined in animals relative to its ability to reduce cardiotoxicity
Melatonin’s protection against these conditions has been repeat- of chemotherapies such as doxorubicin and the side effects of 5-flu-
edly confirmed in experimental animals and some in human clinical orouracil on neurobehavioral performance with significance success.
trials. The major bottlenecks for the more frequent examination of Warburg metabolism, which many tumors and other pathological
melatonin in clinical trials are two-fold; melatonin is inexpensive, cells use to enhance proliferation and cellular survival, is a factor in
and the molecule is not patentable. Thus, in the absence of pharma- the development of cancer cell chemo- and radio-resistance. Current
ceutical industry endorsement, funding of clinical trials, especially evidence indicates that this metabolic phenotype is reversed with the
those of long duration which are important to adequately evaluate the use of melatonin; this being the case, melatonin may also re-establish
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consequences of melatonin use, has been a monumental obstacle for chemosensitivity. The proposed rationale for utilizing melatonin as a
scientists/clinicians in the performance of these much-needed trials. potential treatment of cancer include its intrinsic tumor inhibiting
Because of the shortage of funding, most of the clinical trials that have properties, its ability to limit chemotherapeutic toxicity, and due to its
been performed are underpowered, too short a duration, inappropriate apparent reversal of chemoresistance.
melatonin dose, or have provided incomplete endpoints. I have had a High levels of melatonin are not sustained throughout life. By late
front row seat for 60 years in observing the progress of research on this middle age, the circadian melatonin rhythm begins to attenuate with
highly beneficial molecule, and to not further test it in appropriate its deterioration continuing during late life such that in most elderly a
clinical trials almost seems unethical. melatonin rhythm is barely discernible.9 Mitochondrial production of
The list of diseases where melatonin has been shown to be of melatonin also is believed to wane. Thus, mitochondria and cells lose
experimental and clinical value is extensive. There are hundreds of an important safeguard against functional degradation leaving them
scientific publications in medical journals supporting its use to com- increasingly vulnerable to dysfunction and disease. The frequency and
bat atherosclerotic plaque formation and the rupture of such plaques severity of disorders that melatonin normally opposes are unequivocal-
in the heart microvascular, with the latter being a frequent cause of ly exaggerated in late life; thus, its diminished levels may be a contrib-
heart attack. Also, the consequence of cardiac arrest relative to tissue uting factor in determining the degree of infirmity. As an example, a
damage is attenuated when melatonin is administered. 10,11 There are recent retrospective epidemiological study provided evidence for this
an equal number of reports documenting its ability to lessen the symp- when it was shown that age-related macular degeneration, a condition
toms of and to defer the progression of neurodegenerative disorders, with a highly oxidizing environment in retinal mitochondria, was sig-
with the bulk of these studies being focused, but not exclusively, on nificantly delayed in individuals who had regularly used melatonin in
Alzheimer’s and Parkinson’s diseases.5 Due to its anti-viral actions, previous years.7 While the loss of melatonin may be consequential to
more than 250 publications have encouraged the use of melatonin the enhanced rate of physical and mental regression in the elderly due
to treat viral infections including COVID-19, as well as symptoms to both its reduced circadian regulatory actions and its disease resis-
of post-COVID, with a few small inadequate trials in humans that tance functions, loss of melatonin is not the only feature that deter-
yielded some success. Given that bone loss during aging involves mines the impairment of health span.
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osteoclastic-mediated free radical destruction of bone matrix, its use A discussion about the loss of melatonin with age and its use to
in both experimental and clinical trials have proven melatonin’s utility blunt the frequency or the progression of age-associated debilitating
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