Why are aging and stress associated with dementia, cancer, and other diverse medical conditions? Role of pineal melatonin interactions with the HPA axis in mitochondrial regulation via BAG-1

Pineal melatonin and the cortisol awakening response (CAR) are integral aspects of the circadian rhythm. Pineal melatonin release during sleep is proposed to optimize mitochondrial function and dampen any residual oxidant and inflammatory activity. Little is known about CAR, which is generally thought to prepare the body for the coming day, primarily through the activation of the glucocorticoid receptor (GR). Melatonin, like the gut microbiome-derived butyrate, suppresses GR nuclear translocation, indicating that pineal melatonin and night-time butyrate may interact to modulate CAR effects via the GR, including CAR priming of immune and glia cells that underpin the pathogenesis of most medical conditions. Cutting edge research shows that the GR can be chaperoned by bcl2-associated athanogene (BAG)-1 to mitochondria, where GR can have significant and diverse impacts on mitochondrial function. A number of lines of evidence indicate that melatonin indirectly increases BAG-1, including via epigenetic mechanisms, such as derepressing miR-138 inhibition of BAG-1. The dramatic decrease in pineal melatonin production over aging will therefore have significant impacts on GR nuclear translocation, but also possibly the levels of BAG-1 mediated mitochondrial translocation of the GR. This may have dramatic consequences for how CAR ‘prepares the body for the coming day’, via the differential consequence of GR location in the cytoplasm, nucleus or mitochondria, with differential effects in different cell types. The interactions of melatonin/butyrate/BAG-1/GR are especially important in the hypothalamus, where a maintained heightened melatonin concentration occurs over the night due to the direct release of pineal melatonin, via the pineal recess, into the third ventricle. The interaction of melatonin/butyrate/BAG-1/GR will have differential effects in different cell types, thereby altering the intercellular homeostatic interactions in a given microenvironment that will contribute to the pathogenesis of many aging-associated conditions, including neurodegenerative conditions and cancer. This reframes the nature of the circadian rhythm as well as how stress-associated hypothalamus-pituitary-adrenal (HPA) axis may modulate both the pathogenesis and course of diverse medical presentations. This has a number of research and treatment implications across a host of current medical conditions.