It's interesting to note that when the metabolic environment, as defined by acidity by lactate from glycolysis, that taking magnesium works against the restoration of metabolic respiration. Other measures to restore metabolic respiration may be better, subject to individual context. Such as breathing carbogen (to restore acid-base balance) or taking methylene blue (to counter metabolic blockage, or enable more LL-37 production (to counter endotoxemia).

@alfredoolivas said: Blocking calcium channels is anti estrogenic. Potentiates tamoxifen too https://pubmed.ncbi.nlm.nih.gov/1676580/ https://www.sciencedirect.com/science/article/abs/pii/0006295294905509 Peat tied estrogen to calcium directly. From his 2020 flu newsletter: "A major function of progesterone is the inactivation of the estrogen receptor; estrogen and its “receptor” are powerful activators of cellular calcium uptake". If part of what estrogen does runs through calcium getting into the cell, a channel blocker cutting into it makes sense. The verapamil paper tied its effect to lower P-glycoprotein though, the pump that pushes drugs back out of cells. Could just be tamoxifen staying in the tumor cells longer. Does the second one look at estrogen signaling itself?

@sunsunsun said: using the chart showing increasing pufa consumption correlated to obesity when the increased pufa consumption is in the form of deep frying with seed oils is disingenious The increase in PUFA was driven by seed oils specifically. It's not "disingenuous," it's literarily what happened. While some of that was indeed from deep fried foods, a lot of it was in the form of things like salad dressing, mayo, and replacing things like butter and tallow with canola and soybean oil in regular cooking. And some of it was from a shift in fatty acid composition of livestock fat. Pig fat now has a higher proportion of PUFA than it did in the 1950s, so you are getting more PUFA simply by eating things like bacon or pork shoulder. Besides, deep frying in and of itself is not unhealthy. French Fries used to made mostly with beef tallow. McDonalds used beef tallow for their fries from when they first started until 1990, when they switched to seed oils. And the PUFA content of those seed oils went up again in the early 2000s, when they stopped using partially hydrogenated oils. Deep frying really only becomes problematic when you start using oils that break down at high heats, and considering the high PUFA seed oils are unstable even at room temperature, this change took deep frying from fairly benign to very problematic.. when i see people with really good skin and physiques and overall aura supporting whole food pufa consumption and i see weirdos with bad physiognomies with anime What do you mean by "whole food PUFA consumption?" This is a pretty silly statement, because you will be talking about people who eat about 30 grams less PUFA than the average person. As Ray Peat mentioned, PUFA is unavoidable, outside of a lab created diet. Even 8 ounces of Orange Juice has roughly 100mg of PUFA, and the more saturated fats like dairy fat, beef and coconut have about 2-3% of their fat as PUFA. Those who only consume PUFA in "whole foods" are going to be eating at levels closer to those in the early 1900s on the chart, unless they specifically eat nothing but salmon, flax seed, and nuts. It's true that the vast majority of processed foods today are unhealthy, but that's only because they specifically use toxic ingredients, like high PUFA seed oils, and added iron (aka, ferrous sulfate). If these same foods where made with better ingredients, like beef tallow and coconut oil, they would be more benign, even healthy, and could easily be 20% or less of a healthy diet, that was based around meat, dairy, fruits and such. By the way, how did you ensure these people only consumed PUFA from whole foods? Did you lock them down in a metabolic ward for a few months? Did you review their cronometer data for the past 5 years? Or, did you just hazard a guess about what they eat?

Point Shear Wave Elastography and the Effect of Physical Exercise, Alcohol Consumption, and Respiration in Healthy Adults We found that LSM (liver stiffness measurement) increased significantly following physical exercise, observing clinically significant differences (≥1 kPa) in 1 in 5 subjects. Our study thus supports previous findings, strengthening the hypothesis that physical strain prior to LSM results in significantly higher LSM values and should be avoided prior to measurement. To our knowledge, only one other study has previously investigated the impact of exercise on LSM 8 , but includes only 7 participants. The study found a significant LSM increase 0 and 5 min after activity, while it returned close to baseline values after 10 min. Pulse increase during physical strain has been linked to increased blood flow through the liver, further suggesting that blood redistribution may increase LSM. In line with this, we observed that the increase in exercise-induced LSM was restricted to subjects with a pulse increase >40 bpm, whereas individuals with a low pulse increase (≤40 bpm) did not show signs of increasing LSM after activity, suggesting that only strenuous exercise inducing a high heart rate affects LSM values. Hence, 10 min of rest prior to LSM may be superfluous in most subjects if strenuous exercise is avoided. The low number of individuals (n=9) and short observation time following exercise preclude definitive conclusions, and further studies are warranted to strengthen recommendations regarding rest prior to LSM. Gender differences found in our study, i. e., significant LSM increase observed in males and not in females, also warrant further study to allow conclusions. https://pmc.ncbi.nlm.nih.gov/articles/PMC7723471/

@haidut Ray Peat had a line in his CO2 article that fits this. Naked mole rats and queen bees both live in closed spaces where the CO2 gets up to around 5 or 6 percent, and he wrote "Since queen bees and mole rats live in the dark, I think their high carbon dioxide compensates for the lack of light. (Both light and CO2 help to maintain oxidative metabolism and inhibit lactic acid formation.)" Did the preprint test the infrared at different CO2 levels, or is the CO2 part only in the model so far?

@haidut Ray Peat said almost this in his cholesterol article: "One of the basic functions of cholesterol seems to be the stabilization of mitochondria, preventing their destruction by stress." He tied the synthesis side to energy too: "Serious stress lowers ATP, magnesium, and carbon dioxide. When ATP and intracellular magnesium are decreased, cholesterol synthesis increases." In this study the cells ramped up production once the ER ran short. Did they check whether that ramp-up tracked the cells' ATP, or was the ER shortage enough by itself?

@haidut Ray Peat wrote in his meat physiology article that "an excess of estrogen has been commonly associated with sarcopenia, muscular dystrophy, and atrophy of the skeletal muscles," and that meat scientists were the only people he knew of who called estrogen an anabolic steroid. He also had a cardiolipin point that fits the aging part: in young animals one site of cardiolipin holds palmitic acid, and "After that, as the animal's respiratory activity declines, the palmitic acid is replaced by linoleic acid." Did the paper look at what was in the cardiolipin that was left in the old muscle, or only how much of it there was?

@thebiooracle No, it does not. The data on human diets is not there. P.S. This paper is available as a free PDF download.

Peat called endotoxin "One nearly ubiquitous source of inappropriate excitation and energy depletion" and motor neurons have those really long axons to keep running. Was LBP already high when people were diagnosed, or did it climb as the disease went on?

@AlphaZance said: Stoichiometric Limitation: One molecule of Vitamin E quenches one peroxyl radical before needing to be recycled by Vitamin C or Glutathione. It protects the surrounding bis-allylic motifs as long as active Vitamin E levels are maintained. Hi, Thanks for the post. I've been searching for additonal info, trying to connect the dots. (8 pages docx for an article on my forum). Here is a no-conventional aspect: There is a bidirectional save effect between AA and tocos. Translation of an excerpt: Bidirectional recycling: Once Vitamin E is regenerated (recycled by ascorbic acid), its membrane anchoring allows it to act as a shield; this not only exerts a sparing effect on the nearby ascorbic acid but also enables a bidirectional exchange. The precise mechanism of this reciprocal support remains a complex biochemical challenge, yet the outcome is clear: the two molecules protect and sustain each other amidst the oxidative storm.

@haidut said: ... it may very well be helpful for cancer too. The reason to use B3 in this study was explained, in part, by its prior use for skin cancer prevention: "In a phase III randomized, placebo-controlled trial by Chen et al, [8] oral nicotinamide administered at 500 mg BD for 12 months was safe and effective in reducing the incidence of nonmelanoma skin cancer and actinic keratoses in individuals who were at high risk. " [8] Chen AC, Martin AJ, Choy B, et al. A phase 3 randomised trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med 2015; 373(17):1618–1626. doi: https://doi.org/10.1056/NEJMoa1506197

@haidut Interesting find -- thankss! Yet another reason to keep the glucose uptake high and to avoid metabolic stess. From this paper's concluding passages [bold-facing is mine]: "These results also have implications for therapeutic strategies that manipulate cyst(e)ine availability. Intracellular cysteine became toxic at concentrations of approximately 1–1.5 mM (Extended Data Fig. 4l), substantially above its normal systemic abundance. In fasting human plasma, free cysteine and cystine are present at approximately 10 µM and 80 µM, respectively, with total cyst(e)ine reaching ~250 µM (refs. 31,32). Thus, the toxic threshold is unlikely to be reached through bulk plasma exposure but may be approached in cells with unusually high cyst(e)ine uptake or impaired cysteine disposal. One such example would be cancers with constitutive NRF2 activation that accumulate cysteine beyond biosynthetic demand through upregulation of SLC7A11, promoting the formation of cysteine-derived conjugates that may serve as a detoxification route [33]. Cysteine or NAC has also been reported to induce cell death in glioblastoma and other cellular contexts, particularly during metabolic stress¹¹,³⁴. Our study suggests that, when this buffering capacity is exceeded, or under conditions of metabolic stress such as glucose limitation, excess cysteine becomes deleterious. Conversely, cystine supplementation can enhance tissue regeneration and stem-cell function in some settings.³⁵. Such findings are therefore likely to depend on the capacity of the receiving cells to metabolize or safely dispose of the resulting cysteine. Cysteine damages the mitochondrial electron transport chain via iron–sulfur protein loss, leading to cells relying more on glycolysis for ATP production and trying to uptake more glucose (Extended Data Fig. 4b). This would explain why glucose starvation is synthetically lethal with high cyst(e)ine as exemplified by disulfidptosis, although this death cannot be rescued by iron chelation [10]. Although this process shares features with ferroptosis, it occurs despite elevated GSH and suppressed lipid peroxidation, defining a distinct form of mitochondrial iron-dependent cell death (Extended Data Fig. 4m). Together, these results position thiol imbalance as a central metabolic vulnerability and underscore the importance of both limiting cysteine accumulation and promoting its safe disposal to maintain cellular homeostasis. "

@jamezb46 is it not more likely that this is merely increased excretion rather than increased absorption?

I got some camu camu powder today and put 1/4 tap in some OJ and the effects are nice. Calming energy. And seems to perhaps prevented this late afternoon histamine release I get sometimes. I live in one of the worst cities in the world for seasonal allergies. I will continue with the smaller 100mg doses.

@Mauritio said: @crumblingcookie any new insights ? Yes. Hesperitin seems good and yielding more energy throughout the day in a calm, non-exciting manner through its mitochondria-boosting MoA. Have been taking c. 500mg twice daily. I've been wondering, though, whether the second dose may already be too much (for me in my condition). Still curious about how hesperitin fares in healthier folks in comparison with hesperidin from bergamot extract. Naringin/GSE. Some drops on the tongue quickly made the tongue look rosier and fresher each time. Maybe a good thing before going out and french kissing. Disodium EDTA. Had started with 100mg, then went to 250mg, then 500mg and ultimately 750mg on an empty stomach once daily. Caveat: Really strong chelator of Ca in practice; soon my feet started aching all day as if I had been on a 10miles hike the day before. I suspect decalcification of the foot bones. It still lasted after stopping Na2-EDTA. Distinct improvements each time after supplementing calcium but tbh I can still feel it a month later. Nystatin. IMO 2.5M units (five tablets) four times daily is plenty and there's no use of doing any more like the 5M QID I did. The pharmacy tablets are probably fine. If there's no positive effect from 2-2.5M QID I suggest to look for a different cause. Beyond that, fluconazole for three weeks appears to be a reasonable diagnostic trial or probatory treatment wrt harbouring suspicions of a fungal infection which cannot (yet) be ascertained in other ways, as per Satish Rao MD's proceedings. Although when in suspicion of any extramucosal/extraintestinal fungal involvement I'd escalatate that to 400mg pd instead of a mere 100mg. On the plus side, I really seem to be quite free from any Candida and intestinal biofilm. On the downside, all miseries perdure and it's come to light to actually be Blastomyces disseminated to the brain and cerebrospinal fluid. With the utter dysfunctioning of GI mechanism sort of a last link in the chain of progressive systemic impairments; a final nail in the coffin by general immune exhaustion or centrally-mediated nervous deregulation (reminiscent of that 1930s study where they cut the CNS connection to the ENS). Ah, fun(!) times. What a curveball. Finally explains the headaches beyond all bearing and other things. Doing 700mg pd fluconazole rn while the public health services are passing the buck between factual denial and each other's possible responsibilities with my hopes and expectations in them being severely muted. Fluco is sadly the specifically worst effective azole: Far inferior to double- or triple-dose itraconazole, posaconazole or voriconazole and they are all reported as specifically fungistatic follow-up-treatments after an imperative initiation with i.v. liposomal Amphotericin B. No β-glucan targeting in Blastos because they synthesize α-glucan. On top, blasto yeasts have exceptionally high chitin content. No outer/secreted aspartyl proteases as targets either and no public research on antifungal synergy by inhibition of their internal/vacuolar AsPs. The clinical guidelines handed on the clinically related Cryptococcus btw about are piss-poor and in stark divergence with what's actually known.