Authentic Biochemistry

Aging  and chronic stress can obtain activation of CNS-resident microglia and astrocytes, that produce  type 1 interferons (T1 IFNs) which signal through the heterodimeric IFN-α/β receptor (IFNAR) where receptor binding of  T1 IFNs activates the JAK/STAT thus inducing  IFN-stimulated genes (ISGs) which mediate both pro- and anti-inflammatory functions depending upon the cellular micro-environment.

Now consider how aging is linked to elevated & activated leukocyte counts and it becomes clear that this is a patho-biochemical phenocopy to T cell acute lymphoblastc leukaemia  (T-ALL) where signaling through Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK are shared.

IL7-induced glucocorticoid resistance is diagnostic of certain subtypes of T-ALL and this is also associated with the senescence associated secretory phenotype of aging-linked morbidity and mortality.

Finally, consider that chronic CNS stress leads to increased  glucocorticoid production leading to  a suppression of cell adhesion protein thus corrupting synaptic plasticity, memory re-formation, and cognitive acuity while promoting sarcopenia  by stimulating proteasomal removal of contractile proteins and inhibiting the  PI3-kinase/Akt pathway. Glucocorticoids also prevent IL-2 synthesis and secretion  thus causing immune suppression by blocking T cell activation.

J Neuroinflammation. 2019; 16: 236.

Cytokine & Growth Factor Reviews, 22 Apr 2017, 35:85-96

In this first pre-Christmas present Authentic Biochemistry Podcast lecture, Dr Guerra examines  the multifactorial expansion of NOTCH signalling through early thymocyte development as regulated by paracrine and endocrine hormonal systems in cooperation with  the exemplary plenum of IL7 cytokine mediated signalling through the phosphatidylinositol and AKT kinase cascades.

References

J Cell Physiol. 2003 Mar;194(3):237-55

Development 2019 146: dev172148

Int J Mol Sci. 2020 Nov; 21(21): 7972

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In today's lecture, Dr Guerra explains how subclinical hypothyroidism obtains increased serum thyrotropin (thyroid stimulating hormone, TSH) with flat levels of of free thyroxin (T4) and biologically active free triiodothyronine (T3) in the elderly;β1 adrenergic receptors, sodium/potassium ATPase, voltage-gated potassium channels, malic enzyme and atrial and brain natriuretic factor all respond favourably to thyroxin and hese proteins form the primary architecture of the cardiomyocyte and determine contractile strength. ATP drives muscle contraction/relaxation thus active  mitochondrial nadh  oxidation is essential for healthy aging. Ketone and free fatty acid oxidation decreases with aging while glucose oxidation reciprocally increases while thyroid hormone levels decline with aging, suggesting that myocardial metabolic pathology is linked phenomenologically to subclinical hypothyroidism.

Indeed,thyroid hormone deficiency found in aging populations inhibits fatty acid oxidation through transcriptionally mediated downregulation of PPARα where this transcription factor normally suppresses PDK4, which allows increased PDH. This suggests that aging correlates with decreasing  fatty acid oxidation which is associated with reduced cardiac function.  The aged heart relies on lactate, glucose and pyruvate in place of  fatty acids and the PDH complex plays a central role in the modulation from fatty acid oxidation to glucose oxidation in the mitochondria to finally anaerobic glycolysis in the aging heart.

T lymphocyte maturation and expansion also follows a switch in carbon energy utilization so the two systems function in contrarion regulation, leading to decreased cardiac output with a declining naive T cell population thus losing the regulated induction of inflammation from diverging metabolic sequalae in the aging human.

PLoS One. 2013; 8(6): e65532.

Int J Mol Sci. 2020 Nov; 21(21): 7972

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On this 16th of November Authentic Biochemistry Podcast episode acknowledging my sister Carol's birthday, I explain the MST- kinase mediated transcription factor HIPPO pathway and its potentially gravid linkage to aging associated lymphocyte-informed  autoimmune disease, cancer and neurodegeneration. Published by Dr.. Daniel J. Guerra. 2020

References

Experimental & Molecular Medicine volume 51, Article number: 80 (2019)

Pharmacological Research Volume 143, May 2019, Pages 151-165

Trends in Cancer, May 2019, Vol. 5, No. 5297-307

Nature Reviews Rheumatology volume 13, page389(2017)

Adv Immunol . 2019;144:87-119

During thymic T lymphocyte recombinatorial self avoidance, the  processing  obtained in T cell receptor excision generates small circular DNA byproducts that may be used as a biomarkers for thymic output and for the relative ability of T lymphocytes to fight infection, tumors, and obesity -linked cardiovascular disease and metabolic disorders  that may become important pathologies in the aging human population.

Transcription factors like Nfil3 are important components of this networked  age-related decline called immunosenescence that has the pathobiochemical signatures of SASP , ROS, mutation, epimutation and epigenetic gene expression pathologies.

Dr. Daniel J. Guerra Authentic Biochemistry Podcast Publication. 14 November 2020

References

Braz J Med Biol Res. 2019; 52(7): e8292

PLoS One. 2016; 11(6): e0157930

Experimental & Molecular Medicine volume 51, Article number: 80 (2019)

1.Id proteins are helix-loop-helix (HLH) proteins lacking the basic amino acid domain necessary to bind DNA.and therefore ID  functions in a dominant negative manner by sequestering ubiquitously expressed  or cell- restricted  basic HLH transcription factors: this results in effective blockade of transcription since ID causes a failure  of dimerized basic HLH proteins to bind DNA.

2. Id proteins  regulate transcription factors that are involved in developmental processes such as myogenesis, neurogenesis, bone morphogenesis, lymphopoiesis hematopoiesis, and myeloid differentiation

3. Id2−/− mice lack lymph nodes and Peyer's patches*,

*Peyer's patches are discrete masses of lymphatic tissue found throughout the ileum of the mammalian small intestine

Oncogene volume 22, pages1–9(2003)

PNAS January 15, 2019 116 (3) 890-899

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Since epithelial clock gene and  lymphocyte transcription factor Nfil3 expression is elevated in recombination deficient mice  the potential for  increased bacterial populations lining the gut may induce  an expansion of class 3 innate-like T lymphocytes (ILC3) in the small intestine. thus allowing for circadian clock activity maintenance and effective immune clearance of potential pathogens. This observation may provide a potential pathobiochemical link between obesity and the increasing pathophysiology associated with human aging.

Dr. Daniel J. Guerra Authentic Biochemistry Publication 10 November 2020 

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NFIL3 is a critical transcription factor  immunologically linking the microbiome to the  circadian clock and lipid metabolism where the 

Innate Lymphoid Cell subtype 3 and dendritic cells may stipulate the intestinal microfloral  associated  epithelial temporal chronicity.

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Published by Dr Daniel J Guerra, Authentic Biochemistry 09 November 2020

Reference: Science. 2017 Sep 1; 357(6354): 912–916.

Nuclear factor interleukin 3 (NFIL3, also known as E4-binding protein 4, E4BP4) is a repressor of numerous genes. NFIL3 contains a basic leucine zipper domain, comprising amino acids 73–146, among 462 residues; the N-terminal part of this domain directly binds to DNA, while the C-terminal region is responsible for homo- or heterodimerization of the protein. Amino acids 299–363 comprise a transcriptional repression domain where the N-terminal part of this domain directly binds to DNA, while the C-terminal region is responsible for homo- or heterodimerization of the protein and amino acids 299–363 comprise a transcriptional repression domain.

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Dr. Guerra hybridizes multiple strands of published biochemical research to obtain an event ontology for potentiating factors leading to the aging human pathophysio9logical phenotype. 

In this lecture  I include the following detail:

1. Nuclear factor interleukin 3 (NFIL3, also known as E4-binding protein 4, E4BP4) is a repressor of numerous genes. where an N-terminal domain directly binds to its response element, while the C-terminal region is responsible for homo- or heterodimerization to induce a temporally synchronized geometric configuration obtaining as a transcriptional repression domain

2. NFIL3 represses genes by recruiting histone deacetylase 2 and G9a histone methyltransferase in diverse physiological networks including the circadian clock,  acquired immune response, cell fate, and intermediary metabolism.

Papers to read:

Experimental & Molecular Medicine volume 51, Article number: 80 (2019)

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

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