Melatonin and depression

This 2018 Polish review subject was the relationship between melatonin and depression:

“Although melatonin has been known about and refereed to for almost 50 years, the relationship between melatonin and depression is still not clear. In this review, we summarize current knowledge about the genetic and epigenetic regulation of enzymes involved in melatonin synthesis and metabolism as potential features of depression pathophysiology and treatment.

Melatonin has an antidepressant effect by:

  • Maintaining the body’s circadian rhythm,
  • Regulating the pattern of expression of the clock genes in the suprachiasmatic nucleus (SCN) and
  • Modifying the key genes of serotoninergic neurotransmission that are linked with a depressive mood.

Light input causes the release of γ-aminobutyric acid (GABA) by the SCN, and the inhibitory signal is transmitted to the pineal gland to inhibit melatonin production.

Melatonin is produced via the metabolism of serotonin in two steps which are catalyzed by serotonin N-acetyltransferase (SNAT) and acetylserotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and ASMT are key melatonin level regulation factors.

Both melatonin and serotonin are synthesized from the same amino acid, tryptophan. People on a high tryptophan diet (>10 mg/kg body weight per day) have a significantly lower level of depressive symptoms, irritation, and anxiety than people on a low tryptophan diet (<5 mg/kg body weight per day).

To our knowledge, there are only 2 studies in the literature that characterize mRNA expression of ASMT in the peripheral blood of recurrent DD [depressive disorders]. [They] have demonstrated the reduced mRNA expression of ASMT in patients with depression and cognitive impairment. Surprisingly, these studies, despite promising results, have not been replicated. Moreover, no analysis of other melatonin related-genes as potential biomarkers of depression has been provided.

The main monoamine hypothesis of the pathophysiology of depression indicates that depression is induced by a change in the level of ≥1 monoamines such as serotonin, noradrenaline, and dopamine. The evidence for the serotonergic theory is an observation that antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and noradrenaline reuptake inhibitors increase the level of serotonin in the brain.

We focus on serotonin as a neurotransmitter which is a precursor of melatonin synthesis. In a depressed patient, serotonin synthesis is impaired and the poor precursor availability may prevent the formation of an adequate amount of melatonin. However, only a few studies have analyzed the relationship between serotonin and melatonin levels and the correlation with the blood serum.”


At eight cents a day ($.04 for women) melatonin is a cheap and effective supplement.

I hadn’t considered possible antidepressant effects until reading this review. More human studies are needed.

https://www.karger.com/Article/Pdf/489470 “Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status” (not freely available)

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The hypothalamus and aging

This 2018 Korean review discussed aspects of the hypothalamus and aging:

“A majority of physiological functions that decline with aging are broadly governed by the hypothalamus, a brain region controlling development, metabolism, reproduction, circadian rhythm, and homeostasis. In addition, the hypothalamus is poised to connect the brain and the body so that the environmental information affecting aging can be transmitted through the hypothalamus to affect the systematic aging of the peripheral organs.

The hypothalamus is hypothesized to be a primary regulator of the process of aging of the entire body. This review aims to assess the contribution of hypothalamic aging to the age-related decline in body functions, particularly from the perspective of:

  • energy homeostasis,
  • hormonal balance,
  • circadian rhythm, and
  • reproduction,

and to highlight its underlying cellular mechanisms with a focus on:

  • nutrient sensing
  • inflammation,
  • loss of stem cell,
  • loss of proteostasis, and
  • epigenetic alterations.”


The reviewers didn’t consider aging to be an “unintended consequence” of development. This perspective was found in a reference to A study of DNA methylation and age:

“Aging is not and cannot be programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways.

Genetic programs determine developmental growth and the onset of reproduction. When these programs are completed, they are not switched off.

Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”

The epigenetic clock theory of aging cited the same author, and modified his point to say:

“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes.”

This review’s opposite paradigm was:

“The hypothalamus is hypothesized to be a primary regulator of the process of aging.”

Almost all of the details discussed were from rodent studies.


I favor the “unintended consequence” explanation of aging. As detailed in How to cure the ultimate causes of migraines? and its references, the hypothalamus is a brain structure that lacks feedback mechanisms for several of its activities.

This structure develops shortly after conception and has an active prenatal role. The hypothalamus plays its part in getting us developed and ready to reproduce, with several feedback loops being evolutionarily unnecessary.

The hypothalamus perfectly illustrates the point of:

“When these programs are completed, they are not switched off.”

Should hypothalamic activity not winding down when its developmental role is over be interpreted to construe a role that has some other meaning or purpose as we age?

https://www.sciencedirect.com/science/article/pii/S0047637418300502 “Role of hypothalamus in aging and its underlying cellular mechanisms” (not freely available)

The lack of oxygen’s epigenetic effects on a fetus

This 2018 Loma Linda review subject was gestational hypoxia:

“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.

An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypic programming of disease vulnerability later in life.

A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.

With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”

Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.

Hypoxia phenotypes


This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing the influence of the sponsor’s biases, and any directed narrative that ignored evidence contradicting the narrative, and any storytelling.

See if you can match the meaning of the review’s last sentence quoted above with the meaning of any sentence in its cited reference Developmental origins of noncommunicable disease: population and public health implications.

One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the  F2 grandchild and F3 great-grandchild generations.

One omitted topic was gestational hypoxic effects of caffeine. The first paper that came up for my PubMed search of “caffeine pregnancy hypoxia” was an outstanding 2017 Florida rodent review Long-term consequences of disrupting adenosine signaling during embryonic development that had this paragraph and figure:

“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels. 

After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”

The timing of in utero caffeine treatment leads to differences in adult cardiac function, gene expression, and phenotype. Exposure to caffeine from E6.5–9.5 leads the F1 generation to develop dilated cardiomyopathy with decrease % FS and increased Myh7 expression. In utero caffeine exposure from E10.5–13.5 leads to a hypertrophic cardiomyopathy in the F2 generation along with increased % FS and decreased Myh7 expression

Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!

It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?


The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.

My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?

The review acquired the taint of storytelling with the reviewers’ assertion:

“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”

Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.

This is my final curation of any paper sponsored by this institution.

https://www.physiology.org/doi/abs/10.1152/physrev.00043.2017 “Gestational Hypoxia and Developmental Plasticity” (not freely available) Thanks to coauthor Dr. Xiang-Qun Hu for providing a copy.

A dietary supplement that reversed age-related hearing problems in the brainstem

This 2018 Nevada rodent study was on acetyl-L-carnitine’s action in the brainstem:

“We examined age-related changes in the efficiency of synaptic transmission at the calyx of Held, from juvenile adults (1-month old) and late middle-age (18- to 21-month old) mice. The calyx of Held synapse has been exploited as a model for understanding excitation-secretion coupling in central glutamatergic neurons, and is specialized for high-frequency transmission as part of a timing circuit for sound localization.

Our observations suggest that during aging, there is neuronal cell loss in the MNTB [Medial nucleus of the trapezoid body, a collection of brainstem nuclei in an area that’s the first recipient of sound and equilibrium information], similar to previous reports. In remaining synapses of the MNTB, we observed severe impairments in transmission timing and SV [synaptic vesicle] recycling, resulting in timing errors and increased synaptic depression in the calyx of Held synapse. These defects reduce the efficacy of this synapse to encode temporally sensitive information and are likely to result in diminished sound localization.

We orally administered ALCAR for 1 month and found that it reversed transmission defects at the calyx of Held synapse in the older mice.

These results support the concept that facilitators of mitochondrial metabolism and antioxidants may be an extremely effective therapy to increase synaptic function and restore short-term plasticity in aged brains, and provide for the first time a clear mechanism of action for ALCAR on activity-dependent synaptic transmission.


Human brainstem research is neglected, as noted by Advance science by including emotion in research. Evidence from such research doesn’t play well with beliefs in the popular models and memes of human cerebral dominance.

Do you know any “late middle-age” people who have obvious auditory and synaptic deficits? What if some of the neurobiological causes of what’s wrong in their brains could be “reversed by ALCAR?”

Before using this study as a guide, however, I asked the study’s researchers to calculate the human-equivalent dosage. When I translated the “daily dose of ~2.9 g/kg/d” it worked out to several hundred times the 500 mg to 1 g dietary supplement dosage of acetyl-L-carnitine.

The study’s corresponding coauthor replied:

“This is indeed much larger than that normally consumed by humans via dietary supplementation. We are currently working to determine the effective ‘minimal’ dose of ALCAR and alpha lipoic acid, to better assist guidelines for human application of this supplement.”

https://www.researchgate.net/publication/323941877_Age-related_defects_in_short-term_plasticity_are_reversed_by_acetyl-L-carnitine_at_the_mouse_calyx_of_Held “Age-related defects in short-term plasticity are reversed by acetyl-L-carnitine at the mouse calyx of Held”

Resiliency in stress responses

This 2018 US Veterans Administration review subject was resiliency and stress responses:

Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes — manifesting psychopathology in one individual, but having minimal effect, or even enhancing resilience, in another.

We highlight aspects of stress response modulation related to early life development and epigenetics, selected neurobiological and neurochemical systems, and a number of emotional, cognitive, psychosocial, and behavioral factors important in resilience.”

The review cited studies I’ve previously curated:


There were two things I didn’t understand about this review. The first was why the paper isn’t freely available. It’s completely paid for by the US taxpayer, and no copyright is claimed. I recommend contacting the authors for a copy.

The second was why the VA hasn’t participated in either animal or human follow-on studies to the 2015 Northwestern University GABAergic mechanisms regulated by miR-33 encode state-dependent fear. That study’s relevance to PTSD, this review’s subject, and the VA’s mission is too important to ignore. For example:

“Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar.

“It’s difficult for therapists to help these patients,” Radulovic said, “because the patients themselves can’t remember their traumatic experiences that are the root cause of their symptoms.”

The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”

I curated the research in A study that provided evidence for basic principles of Primal Therapy. These researchers have published several papers since then. Here are the abstracts from three of them:

Experimental Methods for Functional Studies of microRNAs in Animal Models of Psychiatric Disorders

“Pharmacological treatments for psychiatric illnesses are often unsuccessful. This is largely due to the poor understanding of the molecular mechanisms underlying these disorders. We are particularly interested in elucidating the mechanism of affective disorders rooted in traumatic experiences.

To date, the research of mental disorders in general has focused on the causal role of individual genes and proteins, an approach that is inconsistent with the proposed polygenetic nature of these disorders. We recently took an alternative direction, by establishing the role of miRNAs in the coding of stress-related, fear-provoking memories.

Here we describe in detail our work on the role of miR-33 in state-dependent learning, a process implicated in dissociative amnesia, wherein memories formed in a certain brain state can best be retrieved if the brain is in the same state. We present the specific experimental approaches we apply to study the role of miRNAs in this model and demonstrate that miR-33 regulates the susceptibility to state-dependent learning induced by inhibitory neurotransmission.”

Neurobiological mechanisms of state-dependent learning

“State-dependent learning (SDL) is a phenomenon relating to information storage and retrieval restricted to discrete states. While extensively studied using psychopharmacological approaches, SDL has not been subjected to rigorous neuroscientific study.

Here we present an overview of approaches historically used to induce SDL, and highlight some of the known neurobiological mechanisms, in particular those related to inhibitory neurotransmission and its regulation by microRNAs (miR).

We also propose novel cellular and circuit mechanisms as contributing factors. Lastly, we discuss the implications of advancing our knowledge on SDL, both for most fundamental processes of learning and memory as well as for development and maintenance of psychopathology.”

Neurobiological correlates of state-dependent context fear

“Retrieval of fear memories can be state-dependent, meaning that they are best retrieved if the brain states at encoding and retrieval are similar. Such states can be induced by activating extrasynaptic γ-aminobutyric acid type A receptors (GABAAR) with the broad α-subunit activator gaboxadol. However, the circuit mechanisms and specific subunits underlying gaboxadol’s effects are not well understood.

Here we show that gaboxadol induces profound changes of local and network oscillatory activity, indicative of discoordinated hippocampal-cortical activity, that were accompanied by robust and long-lasting state-dependent conditioned fear. Episodic memories typically are hippocampus-dependent for a limited period after learning, but become cortex-dependent with the passage of time.

In contrast, state-dependent memories continued to rely on hippocampal GABAergic mechanisms for memory retrieval. Pharmacological approaches with α- subunit-specific agonists targeting the hippocampus implicated the prototypic extrasynaptic subunits (α4) as the mediator of state-dependent conditioned fear.

Together, our findings suggest that continued dependence on hippocampal rather than cortical mechanisms could be an important feature of state-dependent memories that contributes to their conditional retrieval.”


Here’s an independent 2017 Netherlands/UC San Diego review that should bring these researchers’ efforts to the VA’s attention:

MicroRNAs in Post-traumatic Stress Disorder

“Post-traumatic stress disorder (PTSD) is a psychiatric disorder that can develop following exposure to or witnessing of a (potentially) threatening event. A critical issue is to pinpoint the (neuro)biological mechanisms underlying the susceptibility to stress-related disorder such as PTSD, which develops in the minority of ~15% of individuals exposed to trauma.

Over the last few years, a first wave of epigenetic studies has been performed in an attempt to identify the molecular underpinnings of the long-lasting behavioral and mental effects of trauma exposure. The potential roles of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) in moderating or mediating the impact of severe stress and trauma are increasingly gaining attention. To date, most studies focusing on the roles of miRNAs in PTSD have, however, been completed in animals, using cross-sectional study designs and focusing almost exclusively on subjects with susceptible phenotypes.

Therefore, there is a strong need for new research comprising translational and cross-species approaches that use longitudinal designs for studying trajectories of change contrasting susceptible and resilient subjects. The present review offers a comprehensive overview of available studies of miRNAs in PTSD and discusses the current challenges, pitfalls, and future perspectives of this field.”

Here’s a 2017 Netherlands human study that similarly merits the US Veterans Administration’s attention:

Circulating miRNA associated with posttraumatic stress disorder in a cohort of military combat veterans

“Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced.

PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.”


See the below comments for reasons why I downgraded this review’s rating.

https://link.springer.com/article/10.1007/s11920-018-0887-x “Stress Response Modulation Underlying the Psychobiology of Resilience” (not freely available)

Faith-tainted epigenetics

This 2018 Loma Linda review subject was epigenetic interventions for aging:

“Epigenomic markers of aging, global DNA hypomethylation and promoter-specific hypermethylation may be engendered by iron and HCys [homocysteine] retention.

MiR-29/p53 axis may reverse age-related methylomic shifts, stabilizing both the genome and the epigenome, therefore removing a major risk factor of neurodegeneration. Lowering iron and HCys overload can be accomplished via chelation, blood donation and maintaining an adequate omega-6/omega-3 ratio.”


Sometimes it’s difficult to detect researchers’ biases. If a reader didn’t know about the funding sponsor’s mission:

“Each day we seek to extend the teaching and healing ministry of Jesus Christ”

they may view this paper as unbiased rather than as a directed narrative.

Consider the sponsor’s influence from the perspective of someone seeking treatment for Alzheimer’s disease. If a doctor in this review sponsor’s hospital system recommended chelation treatment, hope would be generated for the patient. Adopting the doctor’s belief about the treatment, though, would be contrary to other evidence per this review:

“In 2008, the NIH chelation trial stopped enrolling patients, approximately two years early.

There is no indication for exposing patients with dementia to the risks of chelation therapy because current chelators cannot help them.”

After reading another review that had this sponsor – The lack of oxygen’s epigenetic effects on a fetus – which also reflected the influence of the sponsor’s biases, and had a directed narrative that ignored evidence contradicting the narrative, and involved storytelling, I’m done curating any paper sponsored by this institution.

http://www.nrronline.org/downloadpdf.asp?issn=1673-5374;year=2018;volume=13;issue=4;spage=635;epage=636;aulast=Sfera;type=2 “Epigenetic interventions for brain rejuvenation: anchoring age-related transposons” (click the pdf button)

The epigenetic clock theory of aging

My 400th blog post curates a 2018 US/UK paper by two of the coauthors of Using an epigenetic clock to distinguish cellular aging from senescence. The authors reviewed the current state of epigenetic clock research, and proposed a new theory of aging:

“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes, the molecular footprints of which give rise to DNAm [DNA methylation] age estimators.

It is best to interpret epigenetic age estimates as a higher-order property of a large number of CpGs much in the same way that the temperature of a gas is a higher-order property that reflects the average kinetic energy of the underlying molecules. This interpretation does not imply that DNAm age simply measures entropy across the entire genome.

To date, the most effective in vitro intervention against epigenetic ageing is achieved through expression of Yamanaka factors, which convert somatic cells into pluripotent stem cells, thereby completely resetting the epigenetic clock. In vivo, haematopoietic stem cell therapy resets the epigenetic age of blood of the recipient to that of the donor.

Future epidemiological studies should consider other sources of DNA (for example, buccal cells), because more powerful estimates of organismal age can be obtained by evaluating multiple tissues..other types of epigenetic modifications such as adenine methylation or histone modifications may lend themselves for developing epigenetic age estimators.”


I’ve previously curated four other papers which were referenced in this review:


The challenge is: do you want your quality of life to be under or over this curve?

What are you doing to reverse epigenetic processes and realize what you want? Do you have ideas and/or behaviors that interfere with taking constructive actions to change your phenotype?

If you aren’t doing anything, are you honest with yourself about the personal roots of beliefs in fate/feelings of helplessness? Do beliefs in technological or divine interventions provide justifications for inactions?

https://www.nature.com/articles/s41576-018-0004-3 “DNA methylation-based biomarkers and the epigenetic clock theory of ageing” (not freely available)