Melatonin Use Rationale for Depression and Dementia

Depression (and dementia) is likely due to metabolically unhealthy cells that have reduced number and reduced functioning mitochondria that result from genes being turned off by epigenetic methylation of gene promoter sites.

Considered here is MELATONIN that declines with age and its positive and protective effect on cell metabolic health.

Melatonin increases Sirt1.

Melatonin directly and indirectly reduces inflammation.

Melatonin is integral to all known forms of DNA repair for nuclear and mitochondrial genes.

Melatonin is integral for correct RNA splicing.

Melatonin turns on methylated genes through HDAC inhibition and direct antioxidant effect.

Melatonin reduces oxidative and nitrosative stress.

Melatonin rich cells have increased number and increased function of mitochondria.

Melatonin rich cells have NO and hTert in excess of H2O2 and have lower level pulses of ROS because of increased expression of antioxidant enzymes.

Melatonin rich cells have homeostasis of mitochondrial fission and fusion proteins and the mitochondria are not skinny or fat but lean and fit.

Melatonin rich cells have reduced markers of cell senescence.

Melatonin rich cells have increased functional integrity and function within tissues and organs.

Melatonin rich cells express lower levels of il-beta 1, caspase and downstream homocysteine and C-reactive protein.

Melatonin rich cells have efficient autophagy with fewer autophagosomes because of healthy maintenance and reduced oxidation and protein  and glycosylation aggregates.

Melatonin rich cells cleave APP in a nontoxic way and beta amyloid is reduced in production and cleared.

Melatonin rich cell state occurs in the young and melatonin poor state occurs with aging.

Cognitive and affective decline is caused by lack of metabolic and gene support that could be improved by supplemental melatonin and its functional mimics.

Melatonin should therefore reverse and prevent depression and dementia in the long term.  Antidepressants are  recommended for 6-18 months of initial therapy duration.

Dale Bredesen, MD reports dementia reversal over 6 months in his treatment algorithm.

I conjecture that melatonin should be adjunctive for initial therapy of MDD and provide monotherapy for prevention and maintenance and over all make our current therapies more effective and more sustaining

http://www.sciencedirect.com/science/article/pii/S0278584616303839

Linking the biological underpinnings of depression: Role of mitochondria interactions with melatonin, inflammation, sirtuins, tryptophan catabolites, DNA repair and oxidative and nitrosative stress, with consequences for classification and cognition - ScienceDirect

The pathophysiological underpinnings of neuroprogressive processes in recurrent major depressive disorder (rMDD) are reviewed. A wide array of biochemical processes underlie MDD presentations and their shift to a recurrent, neuroprogressive course, including: increased immune-inflammation, tryptophan catabolites (TRYCATs), mitochondrial dysfunction, aryl hydrocarbonn receptor activation, and oxidative and nitrosative stress (O&NS), as well as decreased sirtuins and pathway activity. These biochemical changes may have their roots in central, systemic and/or peripheral sites, including in the gut, as well as in developmental processes, such as prenatal stressors and breastfeeding consequences. Consequently, conceptualizations of MDD have dramatically moved from simple psychological and central biochemical models, such as lowered brain serotonin, to a conceptualization that incorporates whole body processes over a lifespan developmental timescale. However, important hubs are proposed, including the gut-brain axis, and mitochondrial functioning, which may provide achievable common treatment targets despite considerable inter-individual variability in biochemical changes. This provides a more realistic model of the complexity of MDD and the pathophysiological processes that underpin the shift to rMDD and consequent cognitive deficits. Such accumulating data on the pathophysiological processes underpinning MDD highlights the need in psychiatry to shift to a classification system that is based on biochemical processes, rather than subjective 

Fixing Molecular Inflammation

Inflamaging results from decreased antioxidant capacity and thereby decreases resilience.

Integral in this process is ROS that trigger the inflammatory cascade of the inflamasome, the innate immune system.  NLRP3, caspase and il-beta 1 form heteromers of inflammation in conjunction with inflammatory molecules notably the c reactive protein.

Macrophages are the sentinels mentioned below.  Microglia cells in brain.  Muller cells in retina. Kuppfer cells in liver. M1 cells in endothelial linings of arteries and veins, respiratory linings, gastrointestinal linings, pancreatic and biliary duct linings.

The most effective upstream fix to molecular inflamaging is increased antioxidant capacity via Nrf2 activators and spermidine/wheat germ enhancement of proteostasis.

Nrf2 activators include melatonin, hydrogen rich water, sulforaphane, spermidine/wheat germ and Green tea extract.

As critical proof of this concept Reversing Dementia accomplished over a thousand times by Dale Bredesen MD of the Buck Institute SHOUTS special cause variation from usual practice.  It signals a paradigm shift to make cells more resilient and resistant to molecular AND injury related  INFLAMMATION!

See his YouTube talk and review his book.  His results are not chance alone.  They are reproducible and have relevance to every organ based specialist and organ based disease model of modern medicine.

http://www.fasebj.org/content/31/5/1787.short

It’s time to redefine inflammation

Maria Antonelli and

+ Author Affiliations

1. ↵1Correspondence: Division of Rheumatology, Case Western Reserve University at MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, Ohio, 44109 USA. E-mail: ixk2@case.edu

Abstract

Inflammation has been defined for many years as the response to tissue injury and infection. We are now forced to reconsider this definition by the avalanche of reports that molecules and cells associated with inflammation are activated or expressed in high concentration in a large variety of states in the absence of tissue injury or infection. Modest increases in concentration of C-reactive protein, a circulating marker of inflammation, have been reported to be associated with an astounding number of conditions and lifestyles felt to be associated with poor health; these conditions represent or reflect minor metabolic stresses. In recent years we have learned that inflammation is triggered by sentinel cells that monitor for tissue stress and malfunction—deviations from optimal homeostasis—and that molecules that participate in the inflammatory process play a role in restoring normal homeostasis. Accordingly, we suggest that inflammation be redefined as the innate immune response to potentially harmful stimuli such as pathogens, injury, and metabolic stress.—Antonelli, M., Kushner, I. It’s time to redefine inflammation.

• C-reactive protein
• unfolded protein response
• homeostasis
• Claude Bernard
• innate immunity

Abbreviations:

CREBH

cyclic AMP response element-binding protein-H

CRP

C-reactive protein

ER

endoplasmic reticulum

TLR

Toll-like receptor

UPR

unfolded protein response

• Received December 12, 2016.
• Ac.

Translational Health Will Likely Become a TwentyFirst Paradigm for Medicine

Does this sound promising to you?

Essentially metabolic health improves resilience to illness and disease.

Strategic change, paradigm change?. 

Cell heal thyself.  Instead of increasing war on threats to health, increase the non war activities of cell building and regeneration.  This acknowledges that the capacity to be resilient and regenerate is magnitudes stronger than powerful medicine.  Properly understood medicines allow the body to recover and thrive post war. Resilience and recovery is an infinite game rather than a finite game that leads to nursing home care.

"Abstract

Advances in geroscience are allowing scientists and clinicians, for the first time, to consider interventions aimed at directly targeting the hallmarks of aging. Unlike disease-specific approaches, such interventions have the potential to prevent multiple diseases of aging simultaneously, thereby greatly enhancing healthspan for most individuals. Initial clinical data indicates that geroprotective compounds such as rapamycin and metformin may be effective at delaying or reversing age-related disease in otherwise healthy elderly people and companion animals. Here I will provide an overview of the field of translational geroscience, which I believe will become the paradigm for the practice of medicine in the 21st century."

My study of cell science strongly indicates that Nrf2 activators and proteostasis activators via appropriate and signaled pathways that ultimately leads to autophagy or cell quality control, Mitophagy and reduced Endoplasmic Reticulum stress will regenerate and optimize resilience to oxidative stress and age related pleiotropic disorders.

The best example of this is the work of Dale Bredesen MD who in the YouTube video Reversing Alzheimer s has reversed dementia in 1000s of patient.  That is too many magnitudes of Lazarus walking out of their tombs of dementia to be chance alone.

Dr. Bredesen eschews the single drug therapy for root cause correction and developed the right strategy, right tactics and right projects to provide a powerful proof of concept.

I think this approach will impact humanity like Tesla's alternating current. (Analogy intended)

Cell power is the flow of electrons and it's safe production.  Not too hot and not to cool, just right.

Horse power is electron power in all its forms.

http://www.sciencedirect.com/science/article/pii/S2468501117300081