The Thymus Is The First To Go... Studies?

[bodacious]

I was listening to one of Ray's interviews last week, I can't remember exactly which one.

He mentioned that, when using FFAs for energy (stressed state), the cells still need a little glucose for energy, and that your body breaks down lean tissue to provide the glucose.

One point that struck me was that the thymus is the first organ to be affected. Assuming this is true,it has huge implications on immunity and autoimmunity.

I can't find any papers to back up this point though. Does anybody know of any?

 

[Dayman]

Here are some along the lines. Still looking for one that shows it is the first to be affected



The thymus is a common target in malnutrition and infection

"Malnutrition, secondary to deficiency in intake of proteins, minerals or vitamins, consistently results in changes in the thymus. This organ undergoes a severe atrophy due to apoptosis-induced thymocyte depletion, particularly affecting the immature CD4+CD8+ cells, as well as a decrease in cell proliferation. This feature is apparently linked to a hormonal imbalance, involving a decrease in leptin and consequent increase in glucocorticoid hormone levels in the serum. The thymic microenvironment is also affected in malnutrition: morphological changes in thymic epithelial cells have been found, together with a decrease of thymic hormone production by these cells. Additionally, intrathymic contents of extracellular proteins, such as fibronectin, laminin and collagens, are increased in thymuses from malnourished children. Taken together, these data clearly point to the notion that the thymus is significantly affected in malnutrition. Similar patterns of thymic changes occur in acute infectious diseases, including a severe atrophy of the organ, mainly due to the apoptosis-related depletion of immature CD4+CD8+ thymocytes. Additionally, thymocyte proliferation is compromised in acutely-infected subjects. The microenvironmental compartment of the thymus is also affected in acute infections, with an increased density of the epithelial network and an increase in the deposition of extracellular matrix. In conclusion, it seems clear that the thymus is targeted in malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered in therapeutic approaches, in both malnutrition and acute infectious diseases."
http://journals.cambridge.org/action/di ... 4507832880




INTERRELATIONSHIPS BETWEEN CARBOHYDRATE, PROTEIN, AND ADENINE NUCLEOTIDE METABOLISM AND CORTISOL EFFECTS ON THESE FUNCTIONS IN VITRO

"Continued maximal levels of incorporation of amino acids into protein in rat thymus cell suspensions require added glucose, a requirement only partially satisfied by other readily metabolized carbohydrate substrates such as pyruvate and lactate. Effects of substrates on incorporation rates correlate with their ability to generate small elevations in ATP above the levels in controls without substrate. The stimulatory effect of glucose occurs prior to its conversion to intracellular pyruvate. The effects of glucose, and other carbohydrates as well, also correlate with glucose 6-phosphate levels. The data suggest a stimulatory role for glycolytic intermediates on amino acid incorporation, mediated possibly through the effects of glycolysis on adenine nucleotides.

Cortisol addition leads to an early inhibition of only the carbohydrate-dependent amino acid incorporation into protein. This hormone effect is associated with a cortisol inhibition of the ability of glucose and other carbohydrates to generate ATP, the effects on ATP in some instances preceding the effects on incorporation. With glucose as substrate, effects of cortisol on amino acid incorporation may be attributed to a prior inhibition of glucose uptake; with lactate and pyruvate as substrate, effects on substrate uptake and on the initial metabolic steps were not found. Although the inhibition of glucose uptake is not the unique action of cortisol, the results suggest that hormonal inhibition at this site has considerable physiological significance. "
http://www.jbc.org/content/244/8/2210.short



Cell-mediated immunity in nutritional deficiency

"Dietary deficiencies of specific nutrients profoundly alter cell-mediated immune responses in man and experimental animals. Both moderate and severe deficiencies are associated with significant changes in immunocompetence. Diets with inadequate levels of protein, calories, vitamin A, pyridoxine, biotin and zinc result in loss of thymic cellularity. Secondary to thymic atrophy, the production of thymic hormones critical for the differentiation of T lymphocytes is reduced, especially in protein-calorie malnutrition and zinc deficiency. Confirmation of a T cell maturational defect in nutritional deprivation comes from the observations of decreased total (T3 and rosette-forming) T cells in the peripheral blood of children with kwashiorkor and marasmus, with preferential loss of helper/inducer (T4) T cell subsets. Reduced number and in vitro function of T cells have also been reported in experimental deficiencies of iron, zinc, copper, and vitamins A and E. Loss of cutaneous hypersensitivity to mitogens and antigens is a consistent sequela of dietary deficiencies of protein, vitamins A and C, pyridoxine, iron and zinc. Cell-mediated immunity directed against allogeneic histocompatibility antigens (e.g. mixed leukocyte cultures, graft versus host, skin graft rejection) may actually be enhanced by experimental protein and polyunsaturated fat deficiencies. Alternatively, pyridoxine, ascorbate and biotin deficiencies resulted in delayed rejection of skin allografts. Cytotoxic T lymphocyte (CTL) activity is impaired in zinc-, iron- and copper-deficient mice, as well as in scorbutic guinea pigs. Natural killer (NK) cell function may be either enhanced or depressed, depending upon the nutrient and its effects on interferon production. Several authors have demonstrated normal or enhanced macrophage activity in a variety of experimental deficiencies. The extrapolation of these observations to infectious disease resistance is not straightforward, and depends upon the nature of the microbe, its own nutrient needs, and the relative importance of innate, as opposed to immunologic, defense mechanisms."
http://europepmc.org/abstract/med/6396715

 

[Dayman]

Effect of Protein Deficiency on Lymphoid Organs in Mice

"The thymus in these mice showed an especially marked decrease in weight of about
85%. "
https://www.jstage.jst.go.jp/article/of ... 5_229/_pdf

 

[aguilaroja]

post 114391 I was listening to one of Ray's interviews... when using FFAs for energy (stressed state), the cells still need a little glucose for energy, and that your body breaks down lean tissue to provide the glucose.
One point that struck me was that the thymus is the first organ to be affected.I can't find any papers to back up this point though...

It is an excellent point.

Usually "modern" medicine "assumes" the thymus shrinks in maturity, so that thymus size is rarely considered, such as in thymomas and some extreme cancer/immune situations. Depleted thymus function and shape are commonly taken as normal in older humans.

Shrinking, or involution, of the thymus with aging has been observed for decades in humans and mammals . I think there was interest in restorative measures for the thymus in part of early and mid last century, but ready journal index databases rarely go back that far.
--
http://www.ncbi.nlm.nih.gov/pubmed/26638690
Biochemistry (Mosc). 2015 Dec;80(12):1629-30. doi: 10.1134/S0006297915120135.
Thymic Involution in Ontogenesis: Role in Aging Program.
Shilovsky GA1, Feniouk BA, Skulachev VP.

"A. V. Khalyavkin considered involution of a thymus as an example of the program of development and further - of proliferation control and prevention of tumor growth. However, in animals devoid of a thymus (e.g. naked mice), stimulation of carcinogenesis, but not its prevention was observed. In this report, we focus on the involution of the thymus as a manifestation of the aging program (slow phenoptosis). We also consider methods of reversal/arrest of this program at different levels of organization of life (cell, tissue, and organism) including surgical manipulations, hormonal effects, genetic techniques, as well as the use of conventional and mitochondria-targeted antioxidants. We conclude that programmed aging (at least on the model of age-dependent thymic atrophy) can be inhibited."

http://www.ncbi.nlm.nih.gov/pubmed/24109481
The effect of age on thymic function.
Palmer DB1.
Front Immunol. 2013 Oct 7;4:316. doi: 10.3389/fimmu.2013.00316.

"Thymic involution is one of the most dramatic and ubiquitous changes seen in the aging immune system, but the mechanisms which underlying this process are poorly understood. However, a picture is emerging, implicating the involvement of both extrinsic and intrinsic factors. In this review we assess the role of the thymic microenvironment as a potential target that regulates thymic involution, question whether thymocyte development in the aged thymus is functionally impaired, and explore the kinetics of thymic involution."

http://www.ncbi.nlm.nih.gov/pubmed/9891234
The role of zinc in pre- and postnatal mammalian thymic immunohistogenesis.
Bodey B1, Bodey B Jr, Siegel SE, Kaiser HE.
In Vivo. 1998 Nov-Dec;12(6):695-722.

"The experimental administration of thyroxin yielded dose dependent results: low doses resulted in thymic hypertrophy, higher doses produced a slight hypertrophy, while the highest employed doses caused thymic atrophy."

"Our radiation, stem cell transplantation, and hormone treatment experiments in animals strongly suggest age and time dependent regeneration of the cytoarchitecture of the thymic cellular microenvironment, as well as intrathymic lymphopoiesis. The human body's zinc pool undergoes progressive reduction, resulting in low zinc plasma levels and a negative crude zinc balance in older rodents, as well as humans. Previous research suggests that the diminished bioavailability of zinc in older mammals may represent one of the major factors for the involution of the thymus and consequent cellular immunological dysfunction."

http://www.ncbi.nlm.nih.gov/pubmed/9427047
Involution of the mammalian thymus, one of the leading regulators of aging.
Bodey B1, Bodey B Jr, Siegel SE, Kaiser HE.
In Vivo. 1997 Sep-Oct;11(5):421-40.
"During the past century of research on the thymus, the fact that every mammalian thymus undergoes marked morphological changes during the complex process of aging has been defined as a basic histogenetical rule. In characterizing the physiological (i.e. chronic) involution of the mammalian thymus, the term "Altersinvolution" referring to age-related involution is used."