Authentic Biochemistry

Since space and time are never the same twice and indeed are relatively uncertain, not even the day/night chronicity is a true cycle. It is a pattern or a familiar sequence of events and nothing more. No two moments are identical and so our internal circadian clock tracks these patterns but the means by which this detection operates at the cellular and molecular level, as well as the event itself involving the revolving celestial bodies in constant flux so in time, the pattern becomes less uniform while the ideal presents as fixed and familiar so to be displayed intentionally and subsequently neurologically as apparent classical experiential phenomena.

Feedback loops compose the ‘molecular clock’ which is governed by a cascading transcription and translational   regulatory mechanisms that are sufficient to maintain circadian rhythms.

Journal of Molecular Endocrinology (2019) 63, R93–R102

The pharmaceutical Remelteon may be a better MT1 MT2 agonist mimetic for decreasing melatonin synthesis in the aging pineal  because it fails to bind MT3 receptor which is an active quinone reductase 2 synthesizing superoxide system. Published 24 October 2020 by Authentic Biochemistry Podcast; Dr Daniel J. Guerra

The artificial enhancement of brain melatonin levels were hoped to suppress the  progress of Alzheimer's Disease in humans  and for correcting the circadian and sleep-wake disturbances associated with advanced aging.. However, given the complex association of melatonin on NAD+ tonicity and this relationship playing a role in DNA Damage Repair Responses (both  SSB and DSB) . melatonin or a surrogate mimetic receptor agonist may have undesirable effects on neurodegeneration and oncogenesis in the CNS and the periphery.

Dr Guerra opens this complex biochemical terrain in this and the previous 21 October Authentic Biochemistry podcast lectures.

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This episode lays the foundation for a common precursor-the essential amino acid L-tryptophan, of both melatonin and NAD+ and the PARP mediated DNA repair pathways linked to tumorigenesis  on one hand and in DNA Damage repair-linked cessation of apoptosis on the other, in the aging  human Central Nervous System.

Cells. 2019 Sep; 8(9): 1047.

Int J Alzheimers Dis. 2011: 741974.

The pineal endocrine hormone melatonin proximally decreasesIL-1β-induced MMP production by inhibiting Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes;  since autoinflammatory  Osteoarthritis (OA) is a degenerative joint (cartilage degradation) disease linked to human aging and Interleukin-1β  contributes to OA pathogenesis by enhancing oxidative stress and inflammation the role(s) of sirtuin and NAD+ metabolism is associated with aging morbidity while also being described in Double-Stranded Break (DBS) DNA Damage Repair (DDR), we have isolated and identified with distinction, pathobiochemical components of the human aging event ontology.

Oncotarget. 2017 Aug 22; 8(34): 55967–55983.

PLOS One .November 25, 2014https://doi.org/10.1371/journal.pone.0113939

Int J Mol Sci. 2019 Mar; 20(5): 1223.

eLife 2020;9:e55828 DOI: 10.7554/eLife.55828

Dr. Guerra offers a deep investigation into the roles of sirtuins in homeostasis , aging and disease as linked to NAD+ metabolism via ecto enzymatic CD38 and intracellular forms of this NAD+ metabolizing enzyme that is associated with T lymphocyte bioenergetics, activation and regulation as embedded within the inflammatory response, disease and aging. Published in Authentic Biochemistry Podcast series on Aging and the immune system. 14 October 2020

Papers mentioned in today's lecture :

Hogan, et al. Front. Immunol., 31 May 2019 |

Cells 2020, 9(1), 228

Camacho-Pereira et al., 2016, Cell Metabolism 23, 1127–1139

Sci. Signal. 10, eaal3024 (2017) 17 October 2017

November 2011 Pharmacological reviews 64(1):166-87

Sirtuins are protein deacetylases with multiple isoforms active in the nucleus, cytosol and mitochondria all serving unique functions and requiring NAD+. These sirtuins function to condense chromatin and yet  protein abundance has less to do with potency than does the availability of NAD+ which can be synthesized from multiple routes. Furthermore, SIRT1 has been associated with  antagonizing age-related decreases in the amplitudes of the SCN output obtaining age-linked differentiating  phases of increases and decreases observed within a circadian cycle..

References:

Int J Mol Sci. 2019 Mar; 20(5): 1223.

PLOS One November 25, 2014 https://doi.org/10.1371/journal.pone.0113939

Circ Res. 2018 Sep 14; 123(7): 868–885

It is proposed that the endocrine hormone melatonin may regulate after its synthesis and secretion from  the pineal gland, the deacetylase acivity of Sirtuin1 to diminish the SASP repertoire of aging and may be linked to common morbidity of pathophysiology linked to COPD and generic Respiratory Distress Syndrome  (RDS)presentation.

Papers of Record in this episode

Int J Mol Sci. 2019 Mar; 20(5): 1223.

Int. J. Mol. Sci. 2014, 15, 16848-16884

International Immunopharmacology Volume 62, September 2018, Pages 23-28

Dr.  Guerra temporally organizes the lecture series toward the dialectical event by mindfully schematizing the SASP , the triad of DNA Damage Repair (DDR)responses, transcriptionally activated  pro-inflammatory cytokine mediated  inflammation, and the pineal-endocrine hormone melatonin circadian clock manifestations  in the biochemistry and physiology of the aging human.

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Lipids, proteins carbohydrates  and nucleotides-may function within  an inflammatory and secretory modality. Thus, the SASP-Senescence-Associated Secretory Phenotype might deliver apoptosis, necroptosis, autophagy, oncogenesis or an extended  senescence sequalae.

An Authentic Biochemistry audio lecture podcast by  Dr. Daniel J. Guerra. 04 October 2020.

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Dr. Guerra

Nature Reviews | Cancer Reviews 19 | AUGUST 2019 :pp. 439

Nature Communications Vol. 9, Article number: 1228 (2018) doi:10.1038/s41467-018-03566-5

Front. Genet., 12 March 2015 https://doi.org/10.3389/fgene.2015.00094