Yay, my first post here!
Wanted it to be about the recent study I did. While the results will have to be replicated with a follow-up experiment, with more animals, and additional groups for comparison, this results has never been seen before with this tumor type, which is 100% lethal and has no known case of spontaneous regression (i.e. disappearing on its own, without treatment). Basically, 2 out of 3 animals were fully cured in this experiment/study.
https://twitter.com/haidut/status/1751716166387597730

Human-equivalent doses for the substances were ~15mg/kg vitamin B1 (thiamine Hcl), 30mg/kg vitamin B3 (niacinamide), 1.5mg/kg vitamin B7 (biotin), and 15mg/kg aspirin. Administration was once daily, orally.

After decades of animal research implicating the serotonin system in the development of all sorts of “addictions”, it looks like a human trial is finally under way. More specifically, a trial with the serotonin receptor 5-HT3 antagonist called ondansetron (named AD04 in the trial), taken orally. Ondansetron is not a new drug and I have been posting about it for years and Ray has been mentioning for even longer. Its typical dosing regimen (for nausea) is 4mg-8mg every 6-12 hours. However, at such doses it can cause severe constipation and even bowel obstruction, and even a serious side effects known as “QT-interval prolongation”, which can increase the risk of sudden cardiac arrest. Curiously, most of the animal studies demonstrating anti-depressant, anxiolytic, anti-Parkinson, anti-cancer and anti-addiction effects used much lower doses, in the human-equivalent dose range of 0.5mg-1mg, which most doctors consider too low to be of any effectiveness. It just so happens that the clinical trial below uses precisely such low-doses – i.e. 0.33mg twice daily. So, it looks like somebody is reading the scientific literature…or Ray’s articles:-)

While this trial is certainly good news, it of course immediately draw attention to the flip side of that coin. Namely, if serotonin is a cause of alcoholism (considered currently incurable) and likely other addictions as well, how can serotonin still be officially promoted by medicine as the “happiness hormone”? Just as importantly, how can SSRI drugs be prescribed like candy, even to toddlers, if their effects are very likely addiction-forming? Considering the ever-growing epidemic of substance abuse (including alcohol) in Western countries, how much of that epidemic is iatrogenic (caused by SSRI drugs) and/or from stress (which raises serotonin)? There is a serious disconnect here and I hope the reformed FDA (that we hear about is in the works) will address this obvious paradox, and not in favor of serotonin/SSRI.

https://www.psychiatrictimes.com/view/positive-results-from-pharmacokinetics-study-of-ad04-for-the-treatment-of-alcohol-use-disorder

“…Adial Pharmaceuticals today announced that it has completed a pharmacokinetics (PK) study of AD04, an investigational genetically targeted, serotonin-3 receptor antagonist, and therapeutic agent for the treatment of alcohol use disorder (AUD) in patients with heavy drinking. This data will help guide the study design for the upcoming phase 3 clinical trial of AD04.1 “Completion of this study achieves our goal to obtain the data we needed to design a more precise and informed phase 3 trial protocol, including evaluating the optimal dosing regimen to maximize the efficacy and safety of AD04 in patients with AUD. Its completion is in accord with previous guidance provided by the FDA and is intended to enhance the likelihood of success in our upcoming phase 3 trial,” said Cary Claiborne, president and chief executive officer of Adial. In this single-center, relative bioavailability, open label study, investigators enrolled a total of 30 healthy adult volunteers in 2 cohorts. Heavy drinking was defined as less than 10 drinks/drinking day. Cohort 1 (n=6) was a randomized, open-label, 2-sequence, 2-period crossover study to evaluate the PK variability of ondansetron from AD04 0.33 and 0.99 mg. Cohort 2 (n=24) was a randomized, open-label, 6-sequence, 4-period crossover study to evaluate the relative bioavailability of the AD04 0.33 mg tablet to a marketed ondansetron 4 mg tablet, dose proportionality of ondansetron PK between AD04 0.33 and 0.99 mg, and the effect of food on the bioavailability of ondansetron administered as the AD04 0.33 mg tablet. Results showed that, because of the lower dose, AD04 0.33 mg delivered lower ondansetron PK exposure than the marketed reference standard ondansetron 4 mg tablet. Furthermore, ondansetron PK exposure increased in proportion to dose across a 3-fold AD04 dose range. Lastly, AD04 can be taken in fed or fasted states.”

https://www.biospace.com/press-releases/adial-pharmaceuticals-announces-positive-topline-results-from-the-ad04-103-pharmacokinetics-study-of-ad04-for-the-treatment-of-alcohol-use-disorder

“…AD04 (0.33mg ondansetron taken orally twice daily) acts upon the 5HT3 pathway and is thought to reduce alcohol craving. This mode of action is distinct from, but complimentary to, the currently approved therapies for AUD.”

Via: http://haidut.me/?p=2722

Years ago, I posted about a study which concluded that vitamin D is as effective as pharma drugs for lowering blood pressure. The doses used in that study were considered pharmacological, but amounted to no more than 4,000 IU daily. The study below corroborates those findings, even in people with obesity, and even with much lower doses of vitamin D. Namely, as low as 600 IU daily may be sufficient to reduce blood pressure, especially in obese people, but I think the optimal dose may be highly dependent on the specific person based on factors such as age, weight, diet, physical activity, medication, etc. Some studies concluded that for certain groups of people doses up to 8,000 IU may be needed to produce the desired benefits, and that the current RDA  for vitamin D established by the FDA were based on several studies that grossly underestimated daily needs by a factor of at least ten (10). So, the 400 IU daily that FDA recommends for adults, may in fact be close to 4,000 IU daily, and that is just to prevent deficiency. Thus, while the study below did not find increased benefit from doses close to 4,000 IU daily, I’d say the jury is still out on that one.

https://doi.org/10.1210/jendso/bvae168

https://scitechdaily.com/vitamin-d-supplements-lower-blood-pressure-in-older-adults-with-obesity-study-finds/

“…New research published in the Journal of the Endocrine Society suggests that vitamin D supplements may help lower blood pressure in older adults with obesity. However, taking doses higher than the Institute of Medicine’s (IOM) recommended 600 International Units (IU) per day does not appear to provide additional health benefits. Vitamin D deficiency is widespread globally and has been linked to increased risks of heart disease, immune disorders, infections, and some cancers. While prior studies have associated vitamin D deficiency with a higher likelihood of hypertension, the overall effect of vitamin D supplementation on blood pressure remains unclear. “Our study found vitamin D supplementation may decrease blood pressure in specific subgroups such older people, people with obesity, and possibly those with low vitamin D levels,” said Ghada El-Hajj Fuleihan, M.D., M.P.H., F.R.C.P., of the American University of Beirut Medical Center in Beirut, Lebanon. “High vitamin D doses compared to the IOM’s recommended daily dose did not provide additional health benefits.”

Via: http://haidut.me/?p=2720

If there is any doubt just how dangerous low metabolic rate can be, the study below should help dissipate such doubts. The study found that (sub)clinical hypothyroidism resulted in severe heart and kidney fibrosis, as well as muscle breakdown, in just 6 weeks after induction. The study induced the hypothyroidism pharmacologically, but the drug used to induce it is not known to cause such negative effects directly, so it was certainly the low metabolic rate that caused the organ dysfunction and whole-body degeneration. Remarkably, the oral administration of vitamin D managed to ameliorate and prevent most such dysfunction/degeneration, when administered over the same 6-week period. The human-equivalent doses were 15 IU / kg and 75 IU / kg body-weight daily, with the higher dose being more effective. The study is very new so I don’t yet have access to the full text, but when I managed to read it in full I will post the specific metrics of how effective vitamin D was.

http://dx.doi.org/10.1007/s00210-024-03593-8

“…There are several interactions between thyroid hormones (THs) and kidney and heart function. Consequently, THs deficit results in profound changes in renal and cardiac function regulation. Interestingly, emerging evidence suggests that vitamin D (Vit D) may benefit to fibrotic lesions in various tissues. Herein, this study was designed to investigate the potential impact of Vit D on renal and cardiac fibrosis in hypothyroid rats. Forty male Wistar rats were divided into four groups as follow: control, hypothyroid (0.05% PTU in drinking water), and hypothyroid + Vit D (PTU and doses of 100 or 500 IU/kg/day, by gavage) groups. After 6 weeks, biochemical parameters such as creatinine and urea in serum samples, and oxidative stress markers including malondialdehyde (MDA), total thiol groups, and superoxide dismutase (SOD) in renal and cardiac tissues homogenate were measured. Also, renal and cardiac fibrosis was evaluated histologically using Masson’s trichrome staining. Hypothyroidism significantly increased creatinine and urea. Also, in hypothyroid group renal and cardiac fibrosis as well as MDA were increased, while anti-oxidative markers including total thiol group and SOD were decreased. Administration of Vit D significantly improved these alterations in oxidative stress markers and fibrosis in renal and cardiac tissues. In conclusion, this study highlighted that Vit D supplementation reduced renal and cardiac fibrosis and improved oxidative stress. These results support the emerging experimental findings linking Vit D being introduced as a potential therapeutic agent.”

Via: http://haidut.me/?p=2718

Linus Pauling is probably smiling while he is looking down upon us from above. High-dose vitamin C as treatment for cancer was one of the most controversial suggestions he was known for, and not only made him many enemies in the medical world, it also partially tarnished his reputation as a Nobel Prize laureate. He is also considered the father of so-called orthomolecular medicine, which is still derided by mainstream medicine as pseudo-scientific and false. Of course, as most of my readers know by now, whatever is labelled “controversial” by mainstream medicine often turns out to be true/right. Despite mocking vitamin C treatment for cancer, without much fanfare certain pharma companies have developed drugs based on vitamin C, with perhaps the most successful to date being the drug Apatone (a combination of vitamin C and vitamin K). Apatone has already been allowed by the FDA to be used on cancer patients including on people with advanced/terminal prostate cancer. So, it is becoming more and more obvious Dr. Linus was right, and just as importantly, the bioenergetic theory of cancer is also right. The study below on pancreatic cancer proposes that vitamin C works by generations hydrogen peroxide (H2O2), which works through the same cytotoxic mechanism as traditional chemotherapy. In other words, medicine reluctantly admits that vitamin C works, but counters any attacks against its approach by claiming that vitamin C is simply another form of cytotoxic chemotherapy. As such, it is used not as a primary treatment, but as an add-on therapy which just increases the potency of traditional chemotherapy. However, if one looks at the published studies on Apatone, a completely different mechanism is proposed – a bioenergetic one. Namely, when vitamin C is combined with an oxidizing agent – vitamin K (as in the drug formulation) or any other quinone-like molecule such as methylene blue, CoQ10, emodin, the tetracycline antibiotics, etc – it gets oxidized to something known as dehydroascorbic acid (DHAA), which itself is a powerful oxidizing agent. Since the vitamin C molecule is structurally very similar to sugar/glucose, it is preferentially uptaken by cancer cells through the same pathways as glucose (e.g. the GLUT proteins), as cancer cells are known to have much higher glucose affinity compared to non-cancer cells. In fact, it is this preferential uptake of glucose by cancer cells that is used both for cancer diagnosis (imaging with radioactive glucose) and has led medicine to keep claiming that cancer is “addicted” to sugar and that carbohydrate restriction, keto diets, fasting, etc should treat cancer. All such approaches have been tried, with disastrous results, as after a brief pause in growth, the cancer becomes highly aggressive and invariably lethal. The bioenergetic theory states that cancer cells uptake more glucose from the blood because they are functionally deficient in glucose. Namely, the glucose that enters cancer cells gets “wasted” by conversion into lactate, due to the cancer cells’ highly reductive state (e.g. low mitochondrial NAD+/NADH ratio) instead of being combusted through OXPHOS. So, the solution would be to provide more glucose, not less. Be that as it may, the Apatone approach is to use a molecule (vitamin C) that uses the same uptake/transport mechanisms as glucose, which results in its preferential accumulation inside cancer cells, and once inside the cancer cell this oxidized form of vitamin C (DHAA) corrects the reductive excess of cancer cells, and after some time they start to respire normally. In other words, Apatone works by converting “cancer” cells back into “normal” cells by gradually changing the redox state of such cells from high reduced to highly oxidized. Why the quotes? Well, it should be clear by now that there is no such thing as a “cancer” cell and a “normal” cells. There is only a continuous spectrum of metabolic health with “cancer” at one end and “health” at the other, with the cell moving back and forth along that spectrum, entirely based on its environmental influences (no mutations needed). However, in order for that process to work the reduced form of vitamin C, which is the one most commonly sold as a supplement, needs to be co-administered with an oxidizing agent (vitamin K, in the case of Apatone) so that DHAA is formed, as DHAA is the true therapeutic agent. Another option is to administer pre-formed DHAA, but that molecule is not very stable and quickly degrades or converts back into the reduced form. Unfortunately, the study below used high amounts of the reduced form of vitamin C (ascorbate) and as such drastically limited its therapeutic potential. While high doses of ascorbate will still raise DHAA formed inside the body, the effects are rather minute compared to administering either preformed DHAA or a combination of vitamin C and a quinone. One can see the vast difference that by comparing the effects of Apatone with the effects seen in the study below. Namely, Apatone as a daily oral dose of just 5g vitamin C (plus 50mg vitamin K) almost completely prevented mortality in patients with end-stage prostate cancer, while a massive 32g daily dose of vitamin C (and by IV route too) merely doubled survival time in patients with pancreatic cancer.  Oh well, I guess it is a step in the right direction and it may be just Big Pharma’s nefarious way to slowly switch over to the metabolic treatment of cancer without admitting culpability along the way. Something similar is already happening with the SSRI industry. Now that is becoming painfully obvious that low serotonin is not the cause of depression and, in fact, high serotonin may be the cause, Big Pharma has started to release SSRI drugs that have substantial anti-serotonin effect at the receptor level. So, such drugs may very well work, but Big Pharma gets to publicly save its theory that SSRI drugs are good and so is serotonin, while implementing the exact opposite hypothesis pharmacologically. In 5-10 years, SSRI drugs will quietly get dropped as “obsolete” and nobody will even think of asking the question of why they were even used in the first place, and how many people were harmed/killed by them. It will be a “paradigm shift” as the good ol’ science philosopher Mr. Kuhn said, which is really just a euphemism for “the jig is up, time to find a new one”.

https://dx.doi.org/10.1016/j.redox.2024.103375

https://medicalxpress.com/news/2024-11-high-dose-iv-vitamin-chemotherapy.html

“…Results from a randomized, phase 2 clinical trial show that adding high-dose, intravenous (IV) vitamin C to chemotherapy doubles the overall survival of patients with late-stage metastatic pancreatic cancer from eight months to 16 months….The findings, published in Redox Biology, mark another success for high-dose, intravenous vitamin C, which has overcome many hurdles in the almost 20 years UI researchers have persevered to demonstrate its benefit for cancer patients. “We’ve had ups and downs, of course, but this is a culmination of a lot of people’s hard work,” says Cullen, who is also a member of UI Health Care Holden Comprehensive Cancer Center. “It’s really a positive thing for patients and for the University of Iowa….”Not only does it increase overall survival, but the patients seem to feel better with the treatment,” Cullen says. “They have fewer side effects, and appear to be able to tolerate more treatment, and we’ve seen that in other trials, too.”

Via: http://haidut.me/?p=2716

Well, duh! This is probably quite obvious to most of my readers, but I am posting it here since most people rarely think of the type of air they are breathing, or consciously select geographical areas based on specific “aeronutrients” (as opposed to gastronutrients) likely to be absorbed there. The study below claims that we absorb a significant amount of essential nutrients, and especially trace minerals, from air and not just food. This may explain the “paradoxes” or why people living in specific areas (e.g. high altitude) and eating a very restrictive diet (e.g. bread and dairy) can not only maintain good health, but thrive and often enjoy strikingly long lifespans (like this youngster, who lived to 168 and died not of old age, but injury/infection). The higher CO2 retention at altitude probably explains a good deal of the health and longevity, but does not explain the lack of nutrient deficiencies that must invariably develop on a restrictive diet. The only possible explanation is that the environment somehow provides those nutrients through a non-gastric pathway, and apparently breathing is a major such pathway. It has been known for millennia that the air in certain locales is unique and therapeutic, even when not at high altitude, and I think the study below provides some ideas why. I have personally noticed that coniferous forests have a profoundly calming and antidepressant effect on me and people around me, and this may be due to the various aromatic terpenes such trees emit in the air. Many of those terpenes raise GABA and/or dopamine, which would explain their anxiolytic and antidepressant effects.

There is also a flip side to that coin – i.e. inhaling air with nefarious ingredients. The dangers of polluted air are well-known, but what I have in mind is something more obscure and ignored even by doctors. Namely, breathing next to or close by people taking various pharmaceutical drugs with known negative effects on health, especially psychotropic drugs such as SSRI, antipsychotics, estrogens, synthetic progestins, etc. Many studies have demonstrated that people taking such drugs exhale measurable quantities of them, and of course people in the physical proximity of the exhaler then inhale those drugs. This could explain many uncomfortable situations where a person in a social setting can cause a profound negative reaction in people around him/her often without any visible behavioral reason. Even without taking any pharmaceutical drugs, sick people are likely to affect people around them through their exhaled breath, which would probably contain high amounts of (of endogenous origin) serotonin, cortisol, estrogen, histamine, nitric oxide (NO), lipid peroxides, etc. This phenomenon can also explain why medical personnel working in specific wards get sicker at much higher rates than the general population and often come down with the same conditions as the patients they take care of (e.g. kidney disease in nephrology wards, liver disease in hepatology wards, cancer in oncology wards, etc). In other words, it is important to be mindful not only of the geographical area and its air composition (and I don’t mean just pollution), but also of the people we associate with and the drugs they take. If you find that somebody you often associate with tends to sour up your mood/digestion/wellness without any obvious effort on their part, it may be the air that they are exhaling (and the pheromones their skin emits), so precautionary measures may need to be taken or contact with the person kept short(er).

https://pubmed.ncbi.nlm.nih.gov/39486624

https://www.sciencealert.com/your-body-can-absorb-vitamins-directly-from-air-evidence-shows

“…When we think of nutrients, we think of things we obtain from our diet. But a careful look at the scientific literature shows there is strong evidence humans can also absorb some nutrients from the air. In a new perspective article published in Advances in Nutrition, we call these inhaled nutrients “aeronutrients” – to differentiate them from the “gastronutrients” that are absorbed by the gut. We propose that breathing supplements our diet with essential nutrients such as iodine, zinc, manganese, and some vitamins.”

Via: http://haidut.me/?p=2714

A very interesting study, and one of the few that I have seen openly acknowledge the existence of the Randle Cycle and its importance to human health. Namely, the study demonstrated that increased FAO is sufficient to cause cellular dysfunction, senescence and ultimately diseases and the process known as “aging”. It is starting to look more and more plausible that aging/disease are nothing but symptoms of increasingly reduced glucose oxidation and increased FAO. As the study says, increased FAO “muscles out” glucose in competition for access to the Krebs/TCA Cycle. This increase in FAO leads to overabundance of acetyl-CoA and the abudance of acetyl group is what the study claims increases the activity of a gene called “p16”, implicated in many chronic conditions associated with aging. However, the study mentioned another mechanism that is mostly ignored by medicine and that mechanisms is the increased reactive oxygen species (ROS) generated by FAO compared to glucose. As discussed on many podcasts, ROS is actually a misnomer and is a symptom of “reductive” rather than “oxidative” stress. In addition, more than 98% of the ROS are generated when there is blockage at one (or more) of steps of the electron transport chain (ETC) and the accumulated electrons start flowing backwards through the chain – i.e. reverse electron flow (REF). REF itself further contributes to the already present reductive stress (low mitochondrial NAD+/NADH ratio) since the actual process of REF further lowers the mitochondrial NAD+/NADH ratio, this lower NAD+/NADH ratio further limits oxidation of glucose and promotes FAO, thus creating a vicious cycle. The buildup of electrons as a result of increased FAO is handled by the cell through an emergency mechanism by converting some of the superfluous acetyl-CoA into citrate and using that citrate to synthesize fat, which is then fed into the beta-oxidation cycle and ends up again as acetyl-CoA – again, a vicious cycle and it just so happens that this metabolic phenotype is the very hallmark of cancer. Medicine now recognizes such metabolic derangement in cancer, but claims that the ETC blocks are due to external agents, cancerous mutations, or just aging in general. But the study below makes it quite clear that the truth is actually backwards and that all that it takes for the “cancer” metabolism to occur is simply a sufficient shift from oxidation of glucose towards FAO, as per the Rande Cycle. This increased FAO results in lowering of the FAD/FADH ratio and thus a functional (co-factor deficiency) block at complex II of the ETC, which ultimately leads to the electron buildup, REF and thus drop in NAD+/NADH ratio as well. In contrast, oxidizing mostly glucose does not generate REF (since it does not lower the FAD/FADH ratio) and when the electrons flow forward it accounts for less than 2% of the total generated ROS during OXPHOS (the other 98% being generated as a result of REF). In other words, all that it takes for both function and structural pathological changes to occur, as well as senescence/aging, is increased FAO at the expense of glucose, which results in a shift of the redox balance in favor of reduction, forming a vicious metabolic cycle.

An interesting finding of the study is that saturated fats (SFA), despite being much preferable than PUFA for oxidation, are also capable of affecting the Randle Cycle and shifting the redox balance in favor of reduction. The specific lipid used in the study to increase FAO at the expense of glucose was octanoate (caprylic acid), and providing sufficiently high concentrations of that SFA was sufficient to trigger the increased FAO and cause senescence. Ray mentioned this on a few podcasts when people asked him if keto diets would be OK if one ate 100% saturated fat. His answer was that a diet which contains only saturated fats in its lipid fraction is preferable to a “standard” Western diet (i.e. 30%+ PUFA on average), however long term consumption of a keto diet with 100% SFA in its lipid fraction is also not optimal since it would generate less CO2, more ROS and ultimately cause the same metabolic derangements as a standard Western diet. Thus, he said, oxidizing primarily glucose is of paramount importance when it comes to systemic health.

In addition, the study contains an interesting finding that a widely used cancer drug known as doxorubicin can produce the exact same metabolic derangements and senescence as the increased FAO, which is another way of saying that the drug is harmful and ultimately (oh, the irony!) carcinogenic. One of the hallmark side effects of standard chemotherapy is that it visibly ages the patient, and the study below provides an explanation why – i.e. most chemotherapy drugs are likely metabolic blockers like doxorubicin and as such not only lead to accelerated aging, but are direct causes of secondary diseases (including cancer), further ruining the patient’s health already compromised by the cancer and its diagnosis. The study exposed another widely used drug – the lipid lowering agent fenofibrate – as also being a pro-senescent agent, and this should not be surprising considering fenofibrate increases FAO. To make matetrs worse, unlike doxorubicin, fenofibrate is used by a much larger group of people as prevention for heart disease (CVD) with (again) the irony being that the drug likely promotes the very disease it is supposed to prevent.

The good news is that this vicious metabolic cycle caused by increased FAO can be broken through various methods that aim at either increasing glucose oxidation, reducing FAO or both. Aside from the increased supply of glucose, substances such as thiamine (vitamin B1), niacinamide (vitamin B3), biotin (vitamin B7), aspirin, oxidizing agents / quinones, thyroid, progesterone, DHEA, pregnenolone, testosterone, DHT, etc all work to increase glucose oxidation, while inhibiting FAO. It just so happens that the first four of the above mentioned substances are the cancer protocol I am using for the xenograft experiments that I have been running for the past 2+ years, and the results so far corroborate both the bioenergetic theory and the findings of the study below. Namely, everything in the body is controlled by metabolism/bioenergetics and oxidizing anything other than (primarily) glucose for an extended period of time ultimately leads to degeneration/disease, and is the primary driver of what we, perhaps mistakenly, call “aging”.

https://doi.org/10.1126/sciadv.ado5887

“…Recent studies have indicated that senescence contributes to aging and age-related diseases (1, 3). p16 expression increases in various tissues with age (7, 8). Increased p16 expression decreases the tissue-regenerative potential of pancreatic β cells and neuronal progenitor cells (2). Moreover, p16-expressing senescent cells that accumulate in the body impair heart and kidney function and shorten healthy lifespan (9). This impaired organ function may be due to the secretion of inflammatory cytokines and chemokines by senescent cells, a phenomenon termed the senescence-associated secretory phenotype (SASP) (10). The link between p16 and aging is further supported by the finding that the INK4/ARF locus, which encodes the senescence effectors p16, alternative reading frame (ARF), and p15, is a hotspot for susceptibility single-nucleotide polymorphisms associated with age-related diseases, such as atherosclerosis and diabetes (1). Therefore, elucidating the regulatory mechanisms of p16 expression may provide clues to understanding the mechanisms of aging. Numerous transcription factors and histone-modifying enzymes have been implicated in p16 expression (6).”

“…We found that upon DNA damage, BNIP3 is phosphorylated by ATM and contributes to an increase in the number of mitochondrial cristae. This increase in cristae enhances the oxidation of fatty acids to acetyl-CoA, an acetyl group donor, thereby promoting histone acetylation around the p16 transcription start site (TSS). Notably, pharmacological activation of FAO alone can induce senescence in fibroblasts, endothelial cells, and mouse liver.”

“…FAO activation decreases acetyl-CoA production from glucose (38). This effect, known as the Randle cycle, is primarily due to inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the mitochondrial enzyme that converts pyruvate to acetyl-CoA (Fig. 4A). Isotope labeling with [U-13C]glucose indicated that the conversion of pyruvate to acetyl-CoA and then to citrate and acetylated amino acids decreased during doxorubicin-induced senescence (fig. S9A). In addition, doxorubicin treatment increased PDH phosphorylation (Fig. 4G and fig. S9, B to D). This increase was attenuated by the knockdown of CPT2, BNIP3, or ATM but not by knockdown of p16. In contrast to doxorubicin treatment, oncogenic RAS expression did not increase PDH phosphorylation (Fig. 4H), perhaps reflecting that PDH phosphorylation is not solely regulated by FAO (39). These results are consistent with FAO activation during DNA damage–induced senescence.”

“…To further investigate the importance of FAO in senescence induction, we used the medium-chain fatty acid octanoate. Unlike the more abundant long-chain fatty acids, octanoate freely crosses mitochondrial membranes (40). When added to cells, octanoate is readily oxidized to acetyl-CoA, an acetyl group donor, and promotes histone acetylation and the associated expression of lipid metabolism–related genes. Treatment of IMR-90 cells with octanoate increased p16, CPT2, and phosphorylated PDH levels and decreased lamin B1 levels (Fig. 5A). In contrast, the ATM-p53-p21 pathway and γH2AX foci were largely unaffected (Fig. 5, A and B). Octanoate treatment increased the percentage of SA-β-gal–positive cells (Fig. 5C). In addition, octanoate treatment decreased the percentage of EdU-positive proliferating cells and increased nuclear size (Fig. 5D and fig. S10A). These changes in cell proliferation and nuclear size were suppressed by p16 knockdown (Fig. 5D). Octanoate treatment increased the expression of inflammatory cytokines and chemokines (fig. S10B). Similar results were obtained with fenofibrate, a lipid-lowering drug that activates FAO through the transcription factor peroxisome proliferator–activated receptor α (PPARα) (Fig. 6, A to E, and fig. S10, C and D) (41). We confirmed that fenofibrate-induced p16 expression was attenuated by CPT2 knockdown (Fig. 6B). Treatment with octanoate or fenofibrate increased mitochondrial ROS levels, decreased mitochondrial membrane potential, and increased the number of cristae and mitochondrial length (fig. S10, E to I).”

“…In this study, we have shown that nuclear DNA damage signaling to mitochondria via BNIP3 induces senescence by activating FAO (Fig. 7L). Our results suggest that DNA damage–activated ATM translocates to mitochondria, where it phosphorylates BNIP3. BNIP3 increases the number of cristae and activates FAO. This activation may reflect an attempt to repair DNA damage through histone acetylation (44). If DNA damage persists, the resulting prolonged FAO activation appears to promote histone acetylation for p16 expression. However, histones are not the only proteins whose acetylation state is regulated by acetyl-CoA levels (45). In addition, FAO activation has effects other than increased acetyl-CoA levels (15, 38, 41). In particular, increased mitochondrial ROS production may contribute to the induction of senescence (12, 46). Further studies are needed to elucidate the mechanisms by which BNIP3 regulates cristae and by which FAO drives senescence. We used doxorubicin and oncogenic RAS, which cause DNA damage (1), to conclude that DNA damage–activated FAO drives senescence. However, we cannot completely exclude the possibility that doxorubicin activates FAO independently of DNA damage.”

Via: http://haidut.me/?p=2710

As many of my readers know, muscle spasticity is one of the main symptoms of low thyroid function and is present in many people with chronic conditions, especially neurological (e.g. multiple sclerosis). A number of remedies have been tried clinically, but there has been no breakthrough, except with quinine. However, for some reason, medicine has decided that quinine is “dangerous” and its use is discouraged clinically while also being regulated in the food supply. Tonic water, which traditionally has 300mg-500mg quinine per quart/liter, has been regulated in most Western countries to contain no more than 100mg per quart/liter. Be that as it may, I think the focus should stay on the fact that impaired muscle relaxation is core symptom of energetic deficiency. As an extreme example, Ray cited experiments from the early 20th century demonstrating that even “rigor mortis” can be prevented with injections of ATP directly into the muscle tissue. The study below found that just 180mcg vitamin K2 (MK-7) daily, for 8 weeks strongly decreased frequency and severity of nocturnal leg/muscle cramps (NLC), while also producing no notable side effects. In addition, the study cites a previous one where vitamin K was able to reduce muscle cramps in hemodialysis patients. The study attributes these effects of vitamin K to its ability to inhibit calcium uptake into the cell from the extracellular medium. I would take this a step further and point out that vitamin K can even reverse already established soft-tissue calcification, which is the reverse process – i.e. pushing calcium out of the cell after it had already accumulated in pathological amounts. However, I think the main mechanism of vitamin K has to be related to its ability to act as a quinone/oxidizer and speed up the flow of electrons through the OXPHOS pathway. In corroboration, T3 administered orally or by injection also has potent muscle-relaxing effects and T3 can also decalcify tissues by raising ATP production (and thus magnesium retention) and accelerating calcium efflux by raising CO2 production (which draws calcium out of the cell as CO2 is leaving the cell) thus achieving higher magnesium/calcium ratio inside the cell. Vitamin K also has this effect and this is probably how it also manages to decalcify cells (an effect already demonstrated in several human trials).

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2825457

https://www.news-medical.net/news/20241030/Vitamin-K2-reduces-the-frequency-intensity-and-duration-of-nighttime-leg-cramps.aspx

“…Half of the confirmed participants were randomly assigned to receive a daily dose of 180 μg vitamin K****2, while the others received a placebo for eight weeks. The placebo and vitamin K2 capsules were identical in appearance and packaging, and both the research staff and participants were blinded to the assignment of groups. Participants consumed one capsule per night and tracked NLC events, pain level, and duration. Research staff contacted them weekly to ensure adherence, collect reports, and enquire about any side effects. The main outcome was the average number of NLCs experienced each week during the eight weeks of the study, with the severity (scored between 1 and 10) and the duration in minutes of the cramps as secondary outcomes.”

“…However, the group receiving vitamin K2 reported that their mean cramp frequency reduced to 0.96 events per week over the eight weeks, while the placebo group’s average number of events increased to 3.63. Statistical tests established that this difference was significant. Those receiving the vitamin capsule also reported greater reductions in the severity of pain and duration of NLC events. No adverse events were reported by the participants related to the consumption of vitamin K2. Following previous findings that vitamin K2 relieves hemodialysis-related cramps, researchers explored whether they can alleviate discomfort from NLCs. They found that from the first week of the trial, vitamin K2 reduced the intensity, duration, and frequency of NLC events. The mechanism could be the lowering of calcium levels, leading to muscle relaxation. Encouragingly, the therapy appeared safe for older adults, with no observed adverse effects during the study. However, it is not recommended for people on certain blood thinners, as it may interfere with its effects.”

Via: http://haidut.me/?p=2708

Yet another confirmation that cortisol, while being life-saving in acute stress situations, can shorten lifespan if chronically elevated. In fact, according to the study below, antagonizing the effects of even normal cortisol levels may extend lifespan. This corroborates Ray’s statement that all the symptoms of aging (and thus every chronic disease) can be reliably reproduced in even youthful organisms by the administration of sufficiently high doses of cortisol. An interesting finding of the study was that the anti-aging effects was due to improved mitochondrial function, so this suggests (again) that any benefit or risk from a specific substance is likely ultimately due to its effects on metabolism/mitochondria. And it just so happens that cortisol does suppress mitochondrial function, while simultaneously enhancing both fatty acid synthesis and fatty acid oxidation, as well as lipolysis. Finally, the study compared the effects of cortisol blocking to the effects of the well-known life-extension drug rapamycin, which works by blocking the mTOR protein. In fact, blocking cortisol extended lifespan by 40%+ more, compared to rapamycin and without the known (and very dangerous) side effects of rapamycin (immunosuppression). The two drugs were not synergistic when used together, suggesting they work through the same pathway.

The anti-cortisol drug the study used was the well-known Mifepristone/RU486. However, there is plenty of evidence that progesterone, DHEA, testosterone, DHT, etc are also capable of antagonizing the effects of cortisol. As a curious example, I would point to both Elon Musk and (especially) Jeff Bezos, who are some of the most well-known users of testosterone (TRT). Both have had doctors and the general public commenting that since starting TRT they have able to “age in reverse” and that is readily visible by comparing pictures from their younger years (20s and 30s) to recent ones. While medicine will probably attribute those beneficial effects on testosterone (T) being an “anabolic” steroid, in reality most of the “anabolism” stems from the anti-catabolic effects of T (it is a cortisol blocker at the receptor level, just like RU486). As such, OTC alternatives with known anti-cortisol effects such as progesterone/DHEA or pregnenolone may also be able to achieve the same effect.

https://doi.org/10.1080/19336934.2024.2419151

https://gizmodo.com/abortion-drug-mifepristone-might-have-unexpected-health-benefits-study-suggests-2000517292

“…The University of Southern California scientists directly compared the effects of mifepristone on female fruit flies with another drug that has shown anti-aging potential, the immunosuppressant rapamycin. They found that both drugs taken separately improved the flies’ longevity, though mifepristone performed a bit better, extending the flies’ lifespan by a median 114% compared to 81% for rapamycin. However, when both drugs were used together on the flies, the flies actually went on to have a slightly lower lifespan than normal—indicating that the drugs work in a very similar way to boost longevity, the researchers said. The team’s other experiments suggest that both drugs do this by improving the cells’ ability to clean up their damaged or dysfunctional mitochondria…”

Via: http://haidut.me/?p=2706

I know the topic of smoking and drinking is controversial, and I hope that this post is not taken as an invitation to start puffing packs a day and downing pints of beer like water. Yet, there is something in the habits of extremely long-lived and healthy people that flies in the face of mainstream medicine and piques my curiosity. On one hand, there is strong evidence that chronic exposure to the aromatic hydrocarbons present in any smoke is carcinogenic, confirmed in many thousands of people who have worked in forest management (controlled fires), furnace/metallurgy workers, chimney sweepers, etc. On the other hand, the evidence for natural tobacco (no additives) smoking is a lot less convincing, even if we factor in the obvious ghostwriting and sponsored studies by the Big Tobacco companies questioning the dangers of smoking. There is also the curious fact that the World Health Organization (WHO) deliberately excludes countries with high tobacco consumption from its reports on cancers and longevity. For instance, not many people know that Caribbean countries, on average, have some of the highest tobacco (and alcohol) consumption per-capita in the world, yet have much lower rates of lung and other cancers, and also have some of the highest numbers of centenarians per-capita in the world. Other countries with a high number of centenarians also seem to have higher rates of smoking (and drinking). In addition, many of the world’s so-called super-centenarians were heavy smokers (and drinkers) throughout their lifetimes. Perhaps the most famous example is former UK Primer Minister Winston Churchill who was a heavy cigar smoker all his life, detested exercise, and was a heavy drinker as well, yet lived well into his nineties despite many of his relatives dying much younger (so genes were probably not a factor).

https://www.scmp.com/news/world/article/1857713/secret-longevity-may-lie-long-lived-smokers-biologically-distinct-group

https://www.dailymail.co.uk/travel/article-7832443/Why-centenarians-abound-Dominica-location-Pirates-Caribbean-films.html

https://www.bbc.com/news/world-africa-44224484

https://www.biorxiv.org/content/10.1101/704080v3.full.pdf

“…The supposed enrichment for extreme-age survival in BZs is then subject to a host of secondary claims, each aimed at explaining the primary pattern of extraordinary longevity. Old-age survival in the BZs is supposed to result from diverse causes such as ‘moderate’ drinking at twice the NHS heavy-drinking guidelines[28], plant-based diets[25–27] and inbreeding[12,13].”

“…However, according to the national statistics bureau of Japan, only 3.9% of Japanese women and 19.3% of men over the age of 80 are smokers[56]. Tokyo centenarians therefore smoke at around twice the rate that could be expected in a younger, 80+year old cohort with an identical sex ratio. Likewise, 80% of the ‘exceptional’ health-status centenarian population were daily drinkers, followed by 49% of the ‘normal’ and less than 40% of the ‘frail or fragile’ centenarians, resulting in “a [significant] positive relationship between drinking habits and functional status”[55]. In contrast with these figures, Japanese government surveys estimate only 2.8% of women and 23% of men aged 80+ drink every day[56]. Daily drinking peaks at 36.7% in men aged 60-69, the heaviest-drinking cohort in Japan[56]. As such, Tokyo centenarians drink at higher rates than any other age group, and smoke at rates equal to a 45-year younger population[56].”

I think there is a play by Woody Allen about a man who falls in coma for decades only to wake up in a hospital at some point in the future and be presented with lit cigar/cigarette by a nurse and upon seeing his shocked face, the nurse exclaims something along the lines of “Please go ahead, it just tobacco. The healthiest remedy known to man.” On a more recent, and grim, note – we do have the extensive data from the COVID-19 pandemic demonstrating convincingly that smokers has a much lower chance of both falling ill with COVID-19, as well as deteriorating and dying from it.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10306417/

“…A case-control study from Mexico included 32,583 patients (12,304 COVID-19 positive cases and 20,279 COVID-19 negative controls) of which 2.3% of cases were smokers and 4.3% of controls had a history of smoking [65]. This study not only concluded that active smokers had a decreased likelihood of developing COVID-19 (females, adjusted OR = 0.49, 95% CI: 0.31–0.78; males, adjusted OR = 0.64, 95% CI 0.51–0.81) but also suggested that nicotine in tobacco might have a therapeutic effect.”

And finally, there is the curious example of a medical student from the UK, who had debilitating ulcerative colitis (UC) – a disease considered “incurable” by medicine – that went away for good when he started smoking a few cigarettes a day.

https://www.dailymail.co.uk/health/article-2201475/Doctors-dont-know-best-Student-claims-cured-debilitating-bowel-disease-taking-smoking.html

“…Stephen Pendry, 23, struggled with crippling pain, tiredness, shortness of breath and dehydration since he was diagnosed with ulcerative colitis four years ago. But he is now completely symptom-free, thanks to a new four-a-day cigarette habit. Doctors are divided over benefits of patients smoking to combat symptoms – some believe nicotine is the healer so patches, and not cigarettes, are way forward”.

So, how can the bioenergetic theory attempt to explain any potential benefits of smoking? Well, for a start, many of the main psychoactive tobacco ingredients (e.g. nicotine, cotinine, anabasine) are aromatase inhibitors.

https://pubmed.ncbi.nlm.nih.gov/3711333/

In addition, it seems that most of the studies that demonstrated detrimental effects from tobacco or nicotine were in-vitro, yet the effects of nicotine/tobacco seem to be the opposite in-vivo, at least in amounts that would constitute smoking a few cigarettes a day. Perhaps most importantly, nicotine seems to be able to strongly blunt the systemic inflammatory effects of endotoxin/LPS, including in humans. Assuming endotoxin/LPS is the main driver of many/most chronic diseases, the anti-estrogenic and anti-endotoxin effects of nicotine (and some other tobacco ingredients) may explain its cumulative effects on promoting longevity, despite the known and undisputed carcinogenic effects of the actual smoke from the burning tobacco.

https://channel.ersnet.org/media-52743-converse-airway-effects-of-nicotine-iin-vitroi-and-iin-vivoi

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.826889/full

https://pubmed.ncbi.nlm.nih.gov/17177960/

“…Because a prototypical ligand for this receptor is nicotine, we studied the in vivo human response to bacterial endotoxin or lipopolysaccharide (LPS) in the context of nicotine or placebo pretreatment. Twelve adult male normal subjects were studied prospectively. Six received overnight transcutaneous nicotine administration by application of a standard patch (7 mg). Six hours later, all subjects were given an intravenous dose of endotoxin (2 ng/kg) and were evaluated for an additional 24 h for circulating levels of inflammatory biomarkers, vital signs and symptoms. The nicotine subjects had elevated blood levels of the nicotine metabolite, continine, prior to and throughout the 24-h post-endotoxin exposure phase. Subjects receiving nicotine exhibited a significantly lower temperature response as well as attenuated cardiovascular responses for 2.5-6 h after LPS exposure. In addition, increased circulating interkeukin (IL)-10 and cortisol levels were also noted in nicotine subjects. These data indicate an alteration in LPS-induced systemic inflammatory responses in normal subjects exposed to transcutaneous nicotine. In this model of abbreviated inflammation, nicotine exposure attenuates the febrile response to LPS and promotes a more prominent anti-inflammatory phenotype.”

Interestingly enough, one of most renowned healers in the Amazonian region – the birthplace of tobacco – used tobacco almost exclusively to heal almost any disease known to man. A key fact to note in his work was that all the tobacco-based remedies he used were used orally and/or topically, but never through smoking.

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.594591/full

“…Harmful usage of tobacco is a public health problem of global concern and, in many countries, the main risk factor for non-communicable diseases. Yet, in the Peruvian Amazon, the geographical region believed to be tobacco’s historical birthplace, this plant is associated with a strikingly different usage and repute: Tobacco (especially Nicotiana rustica L.) in this area is described as a potent medicinal plant, used topically or via ingestion to treat a variety of health conditions. The goal of this transdisciplinary field study was to investigate clinical applications of the tobacco plant as per Amazonian medicine exemplified in the practice of a reputed Maestro Tabaquero, an Amazonian traditional healer whose medical specialization focuses on tobacco-based treatments…The current study described Amazonian therapeutic uses of tobacco (N. rustica L.) in the practice of a Maestro Tabaquero, an accomplished Amazonian healer specializing in tobacco-based treatments. The informant’s descriptions revealed refined knowledge on the plant’s therapeutic scope and properties, safety profile, and application techniques. A liquid remedy taken orally was his most commonly used preparation, with reported acute/sub-acute effects involving a pronounced psychoactive component (altered state of consciousness) and physiological response (emesis, intoxication, Spanish: “mareación”). A skilled tabaquero that knows how to diagnose, dose, administer, and intervene in case of adverse effects was described as imperative for safe treatment delivery; tobacco ingestion otherwise may be dangerous. The main indications mentioned by the informant included problems of the mind, of the respiratory system, parasitic illnesses (intestinal/skin), gout, and Amazonian epistemic conditions described as spiritual-energetic in nature.”

So, maybe that’s the main message here – unmodified tobacco may be indeed a highly beneficial natural remedy, with the benefits present mostly in using the plant through means that do not produce carcinogenic byproducts (e.g. smoking). However, even when smoked it seems that tobacco may still be a good “doctor” (see medical student with UC story above), despite doctors uniformly condemning tobacco/smoking as one of the biggest evils of the modern lifestyle. I wonder how many of the harms of even smoking are due not so much to the undeniably carcinogenic smoke, but to the toxic additives present in the vast majority of commercially sold cigarettes/cigars. The toxic ammonia and the carcinogenic flame retardants that are now mandated in commercial tobacco products by law may very well turn out to be a much bigger villain than the humble leaf from Amazonia.

Via: http://haidut.me/?p=2702

The topic of endotoxin/LPS, 5-HT and gut dysbiosis is a recurring one in the bioenergetic sphere and there is hardly a chronic (and acute – i.e. flu, COVID-19) disease that has not been at least partially linked to our gut bacteria overproducing endotoxin, which then acts on the gut lining – enterochromaffin cells (EC) – to trigger 5-HT, histamine and nitric oxide (NO) production, leading to GI and subsequently systemic inflammation and diseases. As such, keeping the gut bacteria (microbiome) under control with antibiotics, insoluble fiber, charcoal, etc is one of the main mechanisms for improving health in the bioenergetic sphere. Another important aspect in the bionergetic view is that one should consume foods that are easily digestible so that they are absorbs easily and early in the GI tract (stomach and upper small intestine) and do not reach the colon where they would feed the microbiome. There is also a focus on not consuming substances that physically or chemically irritate the intestine (e.g. silica, talc, titanium dioxide, gums, vegetable rennet, etc) since irritation (even without presence of food) would also trigger the same serotonin-histamine-NO-inflammation cascade.

Well, the study below demonstrates why keeping the microbiome in check may be a top priority. It shows that human gut bacteria, at least in babies, produces very high amounts of 5-HT independently of the EC in the gut. In fact, about half of the bacterial species contained in the microbiome (both animal and human) apparently produce 5-HT on their own. That bacterial-derived 5-HT has the role of an immunosuppressant for the baby to dampen allergic reactions. Aside from elucidating an additional major source of 5-HT int the human organism, the study also suggests that “exogenous” serotonin is also bioactive, which is something most doctors still refuse to believe. Namely, medicine has focused mostly on the 5-HT produced by the EC in the gut since they claim that mostly such 5-HT enters the circulation and is of systemic importance. Since the externally (bacterially) produced 5-HT in this study most certainly produced systemic (immune) effects, I think it is pretty clear that exogenous 5-HT matters. That corroborates Ray’s views that one should be careful when consuming foods naturally high in 5-HT such as kiwis, dates, and (unripe) bananas.

https://www.science.org/doi/10.1126/sciimmunol.adj4775

https://www.the-scientist.com/gut-serotonin-curbs-the-developing-immune-system-72265

“…The infant gut is packed with a medley of molecules that dictate development during a critical time in a newborns’ life. But how these molecules interact with and influence immune cells early in life isn’t fully understood. Now, in a study published in Science Signaling, a team of scientists revealed how one molecule produced in the gut, the neurotransmitter serotonin, activates a subset of T cells and dampens the immune system.1 The authors linked gut-derived serotonin to the creation of tolerance against allergens, suggesting that the pathway may play a role in the development of conditions such as asthma and food allergies.”

“…However, when Zeng and her team profiled the metabolites in the gut of neonatal mice, they found that the neonatal intestine had an unexpectedly high amount of the neurotransmitter serotonin. But the serotonin was not coming from the enterochromaffin cells, the cells that produce serotonin in adults, but rather from the gut’s resident bacteria. When they isolated bacteria from both neonatal mice and healthy human infants they found that around half of the microbes in their samples produced serotonin.”

Via: http://haidut.me/?p=2700