This study is encouraging about whether senolytics could cause unintended loss of muscle mass. In mouse studies, that was not the case, but instead muscle mass actually increased.
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It depends whether Senolytics are actually killing off Senescent cells or in fact bringing them back into the mainstream cell cycle.
I personally think a proportion of Senescent cells are cells which have stalled as part of the differentiation process (because of a shortage of acetyl-CoA). If you can get them to differentiate then they will function.
One possible solution to this is to use a Histone Deacetylase Inhibitor. Another is to provide additional acetyl-CoA.
AIUI the issue of senescence results at least in part from the cells ceasing to produce certain proteins. Hence if you get the cells to produce the proteins potentially by using an HDACi then the muscle will grow/be repaired.
Quercetin is an HDACi.
AIUI the only people seriously experimenting on increasing acetyl-CoA are people trying the citrate protocol which makes use of the enzyme ACLY to convert citrate to acetyl-CoA.
Acetyl-CoA has been a clinical marker of tumor growth and metastasis with worse prognosis in cancer patients. We actual try to inhibit acetyl CoA in cancer patients through targeted therapies.
https://www.nature.com/articles/s41568-022-00543-5
In regard to citrate, there is a great deal of literature on cancer’s citrate metabolism. On the one hand extremely high citrate doses show anti-tumor effects but in reality is quite risky to implement in cancer patients for a multitude of reasons, and others have showed that unless you are taking extremely large doses of citrate (which has its own cons) citrate intake actual promotes tumor growth. Some studies showed that: “Citrate uptake can be blocked with gluconate and this results in decreased tumor growth and altered metabolic characteristics of tumor tissue.” That is why many patients supplement specifically with Magnesium Gluconate and Zinc Gluconate (and even HCA garcinia). As a precaution I supplement with Mg Gluconate as well.
Extracellular citrate and metabolic adaptations of cancer cells - PMC.
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I can see there is quite a bit of reading here. It would help if you could give me a link to the:
HCA (garcinia) protocol
In vivo there is always a level of citrate in serum. This is maintained in balance by the metabolism and extra citrate is burnt by the liver. (Liver cells have a particular transport that drags citrate out of serum).
I need, however, to spend some time reading the references before writing more and I may not be able to do that today.
In the end the level of citrate in cells is driven by mitchondrial activity and the expression of the citrate carrier (SLC25A1) which is dependent in part on NF kappa B.
Citrate has an additional complexity in that it inhibits glycolysis.
Acetyl-CoA acts as a form of energy balance indicator. When it is low acetylation will be low and relatively low amounts of mRNA will be transcribed. The difficulty arises when (and I think this is IL-10) the cell has an artificial reduction in the citrate carrier that is not really warranted.
Still I need to read through the links and respond later.
Interestingly, citrate is used for disinfection and in food preservatives against Clostridium botulinum, an anaerobic Gram-positive pathogen [18]. In addition, citrate shows antibacterial activity against other proliferative gram-positive species, such as Staphylococci, and yeast-like fungi, such as Candida albicans [19,20].
Several years ago, we were the first to demonstrate that citrate, a well-known inhibitor of PFK and the Pasteur effect (i.e., anaerobic fermentation in yeast) [24], inhibits the proliferation of various cancer cells of solid tumors (human mesothelioma, gastric and ovarian cancer cells) at high concentrations (10–20 mM), promoting apoptosis and the sensitization of cells to cisplatin [25,26,27].
In line with our hypothesis that a low citrate level promotes the Warburg effect, it has been shown that the inhibition of paclitaxel-resistant lung cancer cells’ proliferation by dichloroacetate is associated with increasing cytosolic citrate concentration [28]. Moreover, citrate level was found depleted in malignant mesothelioma cells (compared to non-malignant cells) [29], and microRNA-126, which suppresses tumor growth, also restored citrate level through the inhibition of ACLY and the Protein Kinase B (also named Akt), a pathway promoting ACLY activation [29].
Citrate inhibits the growth of several xenograft cancer models in mice, increasing the response to chemotherapy. Indeed, daily intra-peritoneal (i.p.) injection of sodium citrate for 4 weeks (15 to 30 mg/kg/day) reduced tumor development in a gastric cancer model (SGC-7901 cells in nude mice), partly by promoting tumor apoptosis [75]. Similarly, in murine tumor models of human osteosarcoma and fibrosarcoma, i.p. injections (two times per week) of citrate (50 to 100 mg/kg), caffeine (50 to 100 mg/kg), and caffeine citrate (100 to 200 mg/kg) reduced tumor growth (with caffeine citrate showing the stronger effect), and all molecules potentiated the anti-tumoral effect of cisplatin treatment [142]. Oral citrate administration also impacts tumor growth. Indeed, oral gavage of citrate sodium (4 g/kg twice a day) for several weeks (4 to 7 weeks) significantly regressed tumors in various murine models, such as subcutaneously implanted syngeneic pancreatic tumor (Pan02), human lung adenocarcinoma (A549 cells) xenografts in nude mice, Ras-driven lung cancer in genetically engineered mouse (GEM), and breast cancer driven by human epidermal growth factor receptor 2/(Her2/Neu) in GEM [77]. Regression of tumors was frequently associated with differentiation and abundant leukocyte infiltration, predominantly constituted of T lymphocytes. Interestingly, plasma citrate levels of these chronically citrate-treated mice were approximately 3 mM, roughly eight times higher than the ones recorded for non-citrate treated mice [77]. A recent study showed that citrate also suppresses growth of PCa xenograft tumors in mice [145]. Of note, in a pancreatic cancer-xenograft murine model, 14 daily doses (500 mg/kg/day) of oral citrate induced the neutralization of TME acidity and potentiated the therapeutic effect of an oral administration of active 5-fluoro-uracil derivative [146].
Furthermore, sodium citrate is also a basic salt, which similarly to bicarbonate, may buffer acidity in TME. This effect favours the penetration of chemotherapy drugs (such as doxorubicin) in cancer cells, also improving the efficacy of mTORC1 inhibitors (rapamycin), and the response to immunotherapies [152,153,154]. The buffering of extracellular acidity could also counteract cancer cells relying on oxidative metabolism, in particular FAO, which is promoted in cancer cells by chronic acidity [109].
For clinical tests, it should be mentioned that citrate has a very low toxicity (see “citrate” PubChem CID 311, at https://pubchem.ncbi.nlm.nih.gov/, accessed on 17 June 2021), as confirmed also by in vivo studies [145], because it is an endogenous metabolite with a complete and rapid metabolism, and thus a very short half-life [160]. However, if administrated in excess, citrate could cause hypocalcaemia, muscle spasms, convulsions, and also a risk of haemorrhage due to its chelating properties of calcium and other divalent cations. These effects can be treated urgently and at best prevented by administration of calcium chloride. By extrapolating the results of a preclinical model [77], the active dose in man would be likely much lower than the one inducing the adverse effects. Clinical trials should determine the mode and duration of citrate sodium administration, its toxicity, and its efficiency. Knowing that numerous patients worldwide have incurable cancers supported by aerobic glycolysis and key oncogenic drivers (such as IGF-1R, Ras/PI3K/Akt, HER2/neu, WNT/β-catenin, TME acidity and EMT) [145,161,162], all pathways efficiently counteracted by citrate sodium in preclinical studies, we strongly believe that the citrate strategy we have proposed since many years [25] should now be considered for clinical trials. In particular, this strategy could increase both the sensitivity to standard chemotherapy drugs and to targeted therapies, whose resistance is mainly supported by the Warburg effect and its oncogenic drivers.
I am not sure what other options there are, but a large proportion of people who have a blood transfusion also have a citrate transfusion. Smaller amounts of citrate are consumed when people eat citrus fruits.
I have found in the papers you cite justification for the argument that citrate has anti-cancer effects. Obviously if a cell has almost no cytosolic acetyl-CoA it will essentially shut down protein production. However, I don’t think we want to shut down the whole protein production system in all cells.