Prolonged fasting reduces inflammation, including TNF-a, in bone marrow, but not in peripheral blood. This is where the confusion around whether fasting reduces inflammation or not comes from. In terms of CML LSC, only what happens in bone marrow matters. During the refeeding period following a fast, TNF-a is reduced even more. So in terms of TNF-a reduction, prolonged-extended fasting is effective.
CML LSCs hide in bone marrow adipose (fat) tissue which absorbs TKI (I wasn't aware of this?!), thus reducing CML exposure to it. It also releases inflammatory agents (e.g. TNF-a) that disable apoptosis (programmed cell death) switch in CML LSCs. This is how BMAT protects CML and drives resistance to TKI.
The quantity of BMAT increases with aging. It has no useful function, beyond energy accumulation, and actually takes up the valuable space normally used by healthy stem cells required for blood regeneration. Its quantity increases during high caloric diet and also during prolonged fasting, but it decreases during normal diet. However, it stops releasing inflammatory agents during fasting.
TKIs' off-target effects drive expansion of BMAT.
BMAT quantity is reduced only by intermittent fasting and exercise.
So it looks like that prolonged intermittent or alternate day fasting for consistent suppression of inflammation and potential BMAT reduction (a month or longer and as often as possible e.g. 4 times a year or simply every day) with occasional extended fasting for deep autophagy and also suppression of inflammation (e.g. once or twice a year for 3-21 days or longer) in combination with regular exercise and strictly low-GI diet could be the way to weaken (turn apoptosis switch back on?) and expose LSCs to TKI and also reduce their protective environment.
I fasted for 87 h and then went for IF for 3 days (20-22h per day) and then switched to ADF (32-38h every 48h) so will se how it goes. IF/ADF is helpful as a preparation for extended fasting as I lost cravings and eat less on refeeding days. I drink salty water now every day. Himalayan pink salt feels great, while iodised sea salt didn't feel good for some reason. After 2 weeks of IF, my monocytes % normalised - they were 16-18 for months.
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Role of bone marrow adipocytes in leukemia and chemotherapy challenges
https://pmc.ncbi.nlm.nih.gov/articles/PMC11105633/
Adipocytes prevent the production of normal HSCs via secretion of inflammatory factors, and adipocyte-derived free fatty acids may contribute to the development and progression of leukemia via providing energy for leukemic cells. In addition, adipocytes are able to metabolize and inactivate therapeutic agents, reducing the concentrations of active drugs in adipocyte-rich microenvironments.
Findings suggest the striking interplay between leukemic cells and adipocytes to create a unique microenvironment supporting the metabolic demands and survival of leukemic cells. Based on these findings, targeting lipid metabolism of leukemic cells and adipocytes in combination with standard therapeutic agents might present novel treatment options.
Observations have shown that leukemic stem cells (LSCs) take refuge in adipose tissue and use it as a niche to support their metabolism. LSCs location in adipose niche creates a pro-inflammatory phenotype for CML cells, resulting in the secretion of cytokines that increase the oxidation of fatty acids in LSCs via increasing lipolysis. LSCs use these FFAs as a fuel source, leading to LSCs quiescence and resistance to chemotherapy [38].
Cytokines and chemokines secreted by BMAs as well as fatty acids might induce proliferation of AML cells [39, 40]. Adiponectin, which is exclusively secreted by adipocytes, is an important regulator of energy metabolism and hematopoiesis.
Adiponectin concentration increases with energy loss, suppressing the expression of adhesion molecules in vascular endothelial cells as well as production of cytokines, which inhibits inflammatory processes through two mechanisms: control of macrophage precursors and suppression of adult macrophage function. Hence, increased adiponectin levels are associated with lower levels of inflammatory markers [41, 42]. Moreover, as a hormone released by adipocytes, adiponectin induces apoptosis by activating caspases and suppressing angiogenesis [43]. In a study by Yokota et al. on adiponectin function in hematopoiesis, it was found that adiponectin inhibits the proliferation of myeloid series and induces apoptosis in myelomonocytic leukemia cells [44].
Adipose tissue is one of the major organs that metabolizes and inactivates drugs, thereby reducing the concentration of active chemotherapy agents in adipocyte-rich microenvironments, such as the bone marrow [75].
Furthermore, as fat deposits shelter ALL cells during chemotherapy, the microenvironment of adipocytes is considered as a protective niche for these cells [77, 78]. On the other hand, treatment of cancer causes a severe increase in total fat in the body. However, these changes reduce the cytotoxic activity of chemotherapy and lead to the emergence of drug-resistant tumor cells, which increases the risk of treatment failure [79]. These findings are of particular importance during leukemia treatment. While several studies on drug resistance have focused on gene mutations in leukemia, some studies have found that leukemia microenvironments play an important role in resistance to chemotherapy. Since adipocytes protect ALL cells from chemotherapy and absorb chemotherapy agents, these cells may migrate to adipose tissue and obtain a survival advantage. ALL cells in this environment remain in a dormant state or receive the survival signal that enables them to resist chemotherapy, which can contribute to an increase in recurrence rates [78].
Generally, adipocytes reduce the accumulation of chemotherapy agents in ALL cells and eliminate them from leukemia environment by absorbing these agents. Adipocytes also metabolize chemotherapy agents, and their enzymes alter the structure of chemotherapy molecules, which results in lower toxicity in ALL cells [75].
Obesity is amongst the main risk factors contributing to poor survival and recurrence rates of ALL and AML [91, 92]. Although localized marrow adipocytes are considered as a supportive factor of leukemic cell proliferation and chemo-resistance, it is suggested that reduced marrow adipocyte content is considered as a good prognostic factor in AML patients during remission. Increased expression and secretion of GDF15 by marrow hematopoietic cells after chemotherapy inhibited MSCs adipogenesis [92]. It can be concluded that obesity and excess adipose tissue can be a preservative pool for LSCs´ proliferation and survival, which make LSCs refractory to chemotherapy. Therefore, reduced marrow adipocyte volume would be a potential therapeutic strategy against leukemia [81, 92].
BMAs release factors such as TNF-α and adiponectin that impair the proliferation of normal hematopoietic cells but contribute to the growth of malignant cells (e.g., MM cells) by inhibiting apoptosis, proliferation, and migration [42, 77]. AML blasts show high growth and proliferation rates in adipocyte-rich environments, and evidence has shown that AML cells rely on adipocytes for survival and proliferation within BM [8]. Studies have also shown that several factors contribute to obesity and recurrence in ALL, including adipocyte secretion, oxidative stress response, and pharmacokinetic changes in chemotherapeutic agents that induce drug resistance [61, 85]. This matter has been of interest for researchers given the role of adipose tissue as a main reservoir of normal HSCs as well as being a poor prognosis factor in obese patients [96]. Such evidence supports the hypothesis that adipose tissue contributes to the protection of cancer cells and the relapse of disease. Pharmacokinetic changes of chemotherapy agents following excessive adiposity, accumulation of lipophilic chemotherapies in adipose tissue that increases the distribution volume and decreases the exposure of cancer cells to chemotherapy factors, increasing accumulation of fat in BM, and excessive increase in body fat during leukemia treatment are in favor of the above hypothesis [75].
In the end, adipocytes change the apoptotic balance of leukemia cells towards survival, increasing the expression of pro-survival signals that reduce cytotoxic activity of chemotherapy agents, lead to emergence of resistant tumor cells, and increase the risk of treatment failure [75, 96].
This work also demonstrated a number of observations in humans, including the remarkable changes in BMAT with acute changes in nutrient intake.
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Relationship between adipocytes and hematological tumors in the bone marrow microenvironment
https://pmc.ncbi.nlm.nih.gov/articles/PMC11543051/
Lipase secreted by adipocytes can inhibit the apoptosis of myeloma cells induced by chemotherapy by increasing autophagy (65). Moreover, in vitro and in vivo, TNF-α and IL-6 can stimulate the proliferation of myeloma cells. Similarly, in myeloma cells, they can also upregulate the expression of C-C motif chemokine ligand 2 (CCL2) (66), which will in turn recruit macrophages that will support cell survival, mediate angiogenesis, and confer multidrug resistance to myeloma cells (67).
Overall, the CCL2/CCR2 signaling pathway affects the biological behaviors of tumor cells, such as survival, proliferation, and migration, and thus cancer development and progression, by regulating multiple downstream signaling pathways (76). This pathway could be one of the potential targets for the treatment of cancer, and its blockade may help to inhibit cancer development and metastasis.
There is a close relationship between BMAs and chemotherapy resistance in hematological tumor cells. The differentiation and maturation of BMAs comprise a dynamic process, which is accelerated after stimulation by external damaging signals, such as chemotherapy. By physically blocking and/or secreting cytokines, adipocytes enriched in the bone marrow protect cancer cells from the cytotoxicity of chemotherapeutic drugs (77).
Similarly, by regulating the growth and apoptosis of tumor cells, adipocytes can also induce drug resistance. Adipocytes were found to lead to cancer cell resistance to vincristine, nilotinib, and zofranil by reducing apoptosis and regulating the cell cycle in ALL cells. Moreover, In AML, Shafat et al. report that AML blasts cocultured with BMA show reduced apoptosis and enhanced proliferation (19). Thus, adipocytes not only physically block the cytotoxicity of chemotherapeutic drugs but also alter the balance of apoptotic signals, increase the expression of pro-survival signals, and ultimately lead to drug resistance in cancer cells, thereby increasing the risk of treatment failure (80).
Although hematological oncology chemotherapy has achieved better clinical outcomes, refractory disease, and recurrence remain the main causes of death in patients with cancer. BMAs are closely associated with the occurrence and progression of hematologic tumors; therefore, targeting the signaling pathways connecting these two cellular entities, such as targeting lipolysis and the oxidative utilization of fatty acids, blocking the energy sources of tumors, or regulating the expression/activity of adipocytokines, might represent valuable strategies for the treatment of hematological tumors (81).
Inhibition of fatty acid oxidative phosphorylation might have a synergistic killing effect on leukemia cells when applied in combination with conventional chemotherapy or targeted therapy. For example, the fatty acid derivative AIC-47 was shown to reduce the expression of the key enzyme for fatty acid oxidation, carnitine palmitoyltransferase 1C (CTP1C), and reverse the imatinib-induced activation of CPT1C and fatty acid oxidation in chronic myeloid leukemia (CML) cells, thus effectively preventing the relapse of CML (88).
In summary, adipocytes are a vital part of the bone marrow microenvironment, influencing the occurrence and progression of hematological cancers. By reprogramming lipid metabolism and the secretion of various adipocytokines, BMAs can influence the proliferation, apoptosis, and chemotherapy resistance of cancer cells. Therefore, targeting lipid metabolism and adipocytokines, based on the pathways of mediating crosstalk activity between cancer cells and BMAs, has the potential to be an important therapeutic approach to inhibit cancer progression, avoid chemotherapy resistance, and improve the overall outcomes of patients with hematological cancers.
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The dynamics of human bone marrow adipose tissue in response to feeding and fasting
https://pmc.ncbi.nlm.nih.gov/articles/PMC8262500/
We demonstrate (a) vertebral BMAT increased significantly during high-calorie feeding and fasting, suggesting BMAT may have different functions in states of caloric excess compared with caloric deprivation; (b) ghrelin, which decreased in response to high-calorie feeding and fasting, was inversely associated with changes in BMAT; and (c) in response to high-calorie feeding, resistin levels in the marrow sera, but not the circulation, rose significantly. In addition, TNF-α expression in marrow adipocytes increased with high-calorie feeding and decreased upon fasting.
The rapidity of energy changes appears to affect BMAT changes.
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Altered metabolomics and inflammatory transcriptomics in human bone marrow adipocytes after acute high calorie diet and acute fasting
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fend...
Secreted proteins in the bone marrow serum, but not peripheral (blood) serum, showed increased anti-inflammatory markers after acute fasting.
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Effect of fasting on human bone marrow adipose tissue
https://www.youtube.com/watch?v=0xLG-YZ8XNs
The number of inflammatory markers increase in peripheral blood, but decrease in bone marrow both during and after fasting. During 10 days fast, TNF-a decreased and only CRP and GDF15 increased in the bone marrow.
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Effects of tki on bone marrow adipose tissue
https://share.google/aimode/k2NdSXtxgfjvakUlH
Tyrosine kinase inhibitors (TKIs) often disrupt the normal balance of the bone marrow microenvironment, frequently pushing mesenchymal stem cells to differentiate into adipocytes rather than bone-forming cells. This leads to an undesirable expansion of marrow adipose tissue (MAT), which can impair healthy blood cell production and weaken bone structure.
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Alternate day fasting effects on bone marrow
https://share.google/aimode/xRck236a2FbwqcI8A
Reduction of Marrow Fat (Adipose Tissue): Unlike continuous severe caloric restriction (which can promote the differentiation of bone marrow stem cells into fat cells and cause bone loss), ADF has been shown to reduce aging-induced bone marrow adipogenesis (marrow fat accumulation). This shift preserves bone marrow stem cell regenerative capacity.
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Exercise effects on bone marrow adipose tissue
https://share.google/aimode/gXgCF8HFyltfP2ypg
Suppresses Fat Accumulation: Exercise prevents and reverses the buildup of marrow fat caused by diet-induced obesity, aging, or certain pharmaceutical treatments.
Enhances Stem Cell Niches: Exercise reduces marrow inflammation and restores healthy hematopoietic (blood cell-forming) functions that are otherwise disrupted by excessive marrow fat.