Increasing serotonin (5-HT) breakdown delays/prevents aging

[haidut]

The naked mole rat (NMR) is one of the most fascinating species. Despite being a humble rodent, much smaller than a regular house/city rat, the NMR has an exceptionally long life-span of 35+ years (compared to 2-3 years for the common rat) and on top of that is remarkably resistant to the effects of aging - i.e. NMR even in their 30s remain very active, fertile and youthful, without any of the chronic diseases affecting the common rat (e.g. cancer, infections, vascular disease, etc). In other words, not only does the NMR live long, it stays biologically young and highly functional for the vast majority of its lifespan. As such, the NMR has been subjected to numerous studies trying to unravel the secrets of its longevity and health. Unfortunately, most such studies try to come up with genetic explanations, despite complete lack of evidence implicating genes. A much simpler explanation for the exception NMR longevity may be the fact that those rodents live in deep burrows that they almost never leave, and as such are chronically exposed to CO2 ambient concentrations that are many-fold higher than the CO2 exposure of the common rat. One of the results of breathing high-CO2 air is increased uptake and degradation of serotonin (5-HT). Aside from 5-HT having a known role in chronic diseases, the study below now demonstrates that 5-HT may also have a crucial role in aging - i.e. it is the uniquely upregulated degradation of 5-HT in the NMR that prevents the accumulation of senescent (old) cells, thus largely preventing the "old" phenotype in these animals regardless of their age. Aside from increasing endogenous CO2 levels, other interventions that may achieve the same effect in humans is intake of substances known to upregulate the activity of the monoamine-oxidase type A (MAO-A) enzyme discussed in the study. Such substances are vitamin B2 (riboflavin), copper, magnesium, progesterone, and androgens. Obviously, reducing 5-HT synthesis is probably an even better approach, and can be achieved by avoiding dietary tryptophan and/or inhibiting its absorption from the GI tract. Gelatin and aspirin are probably the most appropriate interventions for addressing the tryptophan angle.

https://dx.doi.org/10.15252/embj.2022111133
Japanese scientists may have unraveled the secret of aging resistance in naked mole-rats

"...Naked mole-rats have the longest life span among all rodents and can resist aging and the age-related diseases. However, the precise mechanisms underlying this ability are largely unclear. In a new study, Japanese researchers have identified a unique species-specific "natural senolytic" or senescent cell-removal mechanism in NMRs, involving serotonin metabolism and the INK4a-RB signaling axis. Their findings provide useful insights into ways to resist aging and age-related diseases, including cancer. The study is published in The EMBO Journal. Heterocephalus glaber or naked mole-rats (NMRs)—a mammal species native to Eastern Africa—are the longest-living rodents with an exceptionally long lifespan of over 37 years with a unique ability to delay aging and resist age-related diseases, such as cancer. For these reasons, NMRs have attracted a lot of attention, with researchers hoping to unravel the mechanisms contributing to their longevity."

"...The Department of Aging and Longevity Research, Kumamoto University is the only center in Japan which breeds NMRs and conducts research on their resistance to aging and cancer. Explaining the rationale behind their study, Professor Miura, states, "Senolysis or the targeted removal of senescent cells has been shown to inhibit aging-related decline in mice.""

"...They observed that induction of cellular senescence led to cessation of cell proliferation due to arrest of the cell cycle with the activation of INK4a and RB (important factors for induction of cellular senescence), in both NMR- and mouse-fibroblasts. However, only NMR cells gradually and significantly activated cell death, suggesting that senescent cell accumulation in NMRs may be suppressed through their removal. Through further experiments, the researchers observed that there was an accumulation of serotonin (a neurotransmitter that sends signals between nerve cells) in the non-senescent NMR-fibroblasts, but not in the mouse-fibroblasts. Upon senescence induction, in NMR cells, serotonin was metabolized by monoamine oxidase (MAO; an enzyme highly activated in senescent NMR fibroblasts after induction of cellular senescence) and converted to 5-hydroxyindole acetic acid (5-HIAA; a metabolite), releasing large amounts of hydrogen peroxide (H2O2). The team proposed that oxidative stress due to the intracellular production of H2O2 predisposed the senescent NMR fibroblasts to the cell death pathway, thus leading to senolysis (selective removal of senescent cells). This was confirmed by the observation that the addition of MAO inhibitors and antioxidants inhibited cell death in NMR fibroblasts."

"...Furthermore, treatment with the MAO inhibitor significantly suppressed cell death but increased the number of senescent cells only in NMR lung on day 21. This suggests that MAO plays a role in inducing cell death and reducing the number of senescent cells following the induction of cellular senescence in NMR lung cells. These results are consistent with the in vitro findings and suggest that MAO contributes to suppress the accumulation of senescent cells in NMR tissues."

 

[Peater]

I don't understand any of that. Can you just hurry up and release "Ratinil" so I can benefit. Thanks

 

[haidut]

I don't understand any of that. Can you just hurry up and release "Ratinil" so I can benefit. Thanks

No need for Ratinil I already mentioned in the post things like progesterone, androgens, vitamin B2, etc as being helpful.

 

[Peater]

I already mentioned in the post things like progesterone, androgens, vitamin B2, etc as being helpful.

I completely missed that!

 

[dhtsupreme]

Off topic but still related to serotonin. I wanted to ask what would you do if you had auditory hallucinations? I've read every schizophrenia post and it looks like you'd target serotonin, nitric oxide, and ammonia. Is there anything else you would focus on? What would you take if you had it? Curious @haidut

 

[haidut]

Off topic but still related to serotonin. I wanted to ask what would you do if you had auditory hallucinations? I've read every schizophrenia post and it looks like you'd target serotonin, nitric oxide, and ammonia. Is there anything else you would focus on? What would you take if you had it? Curious @haidut

Sorry, I don't provide personal advice. When was the last time you searched the forum for schizophrenia? I just did a post on that topic a few days ago.

Dopaminergic/antiserotonin drug treats schizophrenia - psychiatry is a giant FRAUD!

Some people make take issue with the title and claim that it is too dramatic. In this case, at least, the title may even be an understatement in regards to evidence of just how utterly FRAUDULENT psychiatry is and has been for decades. Speaking of the latter, psychiatry has claimed for decades...

raypeatforum.com

 

[Mauritio]

The naked mole rat (NMR) is one of the most fascinating species. Despite being a humble rodent, much smaller than a regular house/city rat, the NMR has an exceptionally long life-span of 35+ years (compared to 2-3 years for the common rat) and on top of that is remarkably resistant to the effects of aging - i.e. NMR even in their 30s remain very active, fertile and youthful, without any of the chronic diseases affecting the common rat (e.g. cancer, infections, vascular disease, etc). In other words, not only does the NMR live long, it stays biologically young and highly functional for the vast majority of its lifespan. As such, the NMR has been subjected to numerous studies trying to unravel the secrets of its longevity and health. Unfortunately, most such studies try to come up with genetic explanations, despite complete lack of evidence implicating genes. A much simpler explanation for the exception NMR longevity may be the fact that those rodents live in deep burrows that they almost never leave, and as such are chronically exposed to CO2 ambient concentrations that are many-fold higher than the CO2 exposure of the common rat. One of the results of breathing high-CO2 air is increased uptake and degradation of serotonin (5-HT). Aside from 5-HT having a known role in chronic diseases, the study below now demonstrates that 5-HT may also have a crucial role in aging - i.e. it is the uniquely upregulated degradation of 5-HT in the NMR that prevents the accumulation of senescent (old) cells, thus largely preventing the "old" phenotype in these animals regardless of their age. Aside from increasing endogenous CO2 levels, other interventions that may achieve the same effect in humans is intake of substances known to upregulate the activity of the monoamine-oxidase type A (MAO-A) enzyme discussed in the study. Such substances are vitamin B2 (riboflavin), copper, magnesium, progesterone, and androgens. Obviously, reducing 5-HT synthesis is probably an even better approach, and can be achieved by avoiding dietary tryptophan and/or inhibiting its absorption from the GI tract. Gelatin and aspirin are probably the most appropriate interventions for addressing the tryptophan angle.

https://dx.doi.org/10.15252/embj.2022111133
Japanese scientists may have unraveled the secret of aging resistance in naked mole-rats

"...Naked mole-rats have the longest life span among all rodents and can resist aging and the age-related diseases. However, the precise mechanisms underlying this ability are largely unclear. In a new study, Japanese researchers have identified a unique species-specific "natural senolytic" or senescent cell-removal mechanism in NMRs, involving serotonin metabolism and the INK4a-RB signaling axis. Their findings provide useful insights into ways to resist aging and age-related diseases, including cancer. The study is published in The EMBO Journal. Heterocephalus glaber or naked mole-rats (NMRs)—a mammal species native to Eastern Africa—are the longest-living rodents with an exceptionally long lifespan of over 37 years with a unique ability to delay aging and resist age-related diseases, such as cancer. For these reasons, NMRs have attracted a lot of attention, with researchers hoping to unravel the mechanisms contributing to their longevity."

"...The Department of Aging and Longevity Research, Kumamoto University is the only center in Japan which breeds NMRs and conducts research on their resistance to aging and cancer. Explaining the rationale behind their study, Professor Miura, states, "Senolysis or the targeted removal of senescent cells has been shown to inhibit aging-related decline in mice.""

"...They observed that induction of cellular senescence led to cessation of cell proliferation due to arrest of the cell cycle with the activation of INK4a and RB (important factors for induction of cellular senescence), in both NMR- and mouse-fibroblasts. However, only NMR cells gradually and significantly activated cell death, suggesting that senescent cell accumulation in NMRs may be suppressed through their removal. Through further experiments, the researchers observed that there was an accumulation of serotonin (a neurotransmitter that sends signals between nerve cells) in the non-senescent NMR-fibroblasts, but not in the mouse-fibroblasts. Upon senescence induction, in NMR cells, serotonin was metabolized by monoamine oxidase (MAO; an enzyme highly activated in senescent NMR fibroblasts after induction of cellular senescence) and converted to 5-hydroxyindole acetic acid (5-HIAA; a metabolite), releasing large amounts of hydrogen peroxide (H2O2). The team proposed that oxidative stress due to the intracellular production of H2O2 predisposed the senescent NMR fibroblasts to the cell death pathway, thus leading to senolysis (selective removal of senescent cells). This was confirmed by the observation that the addition of MAO inhibitors and antioxidants inhibited cell death in NMR fibroblasts."

"...Furthermore, treatment with the MAO inhibitor significantly suppressed cell death but increased the number of senescent cells only in NMR lung on day 21. This suggests that MAO plays a role in inducing cell death and reducing the number of senescent cells following the induction of cellular senescence in NMR lung cells. These results are consistent with the in vitro findings and suggest that MAO contributes to suppress the accumulation of senescent cells in NMR tissues."

Something that is worth adding to the reasons why naked male rats live so long, is that they have different cell membrane saturation levels than regular rats: they have lower levels of PUFA (espcecially DHA) and higher levels of plasmalogen, which is an endogenous molecule that prevents peroxidative damage. So they are protected twice from PUFA. And the evidence is pretty clear that, the lower the saturation index of an animal ,the longer is their lifespan.

"Phospholipids containing highly polyunsaturated fatty acids are particularly prone to peroxidation and membrane composition may therefore influence longevity. Phospholipid molecules, in particular those containing docosahexaenoic acid (DHA), from the skeletal muscle, heart, liver and liver mitochondria were identified and quantified using mass-spectrometry shotgun lipidomics in two similar-sized rodents that show an approximately 9-fold difference in maximum lifespan. The naked mole rat is the longest-living rodent known with a maximum lifespan of >28 years. Total phospholipid distribution is similar in tissues of both species; DHA is only found in phosphatidylcholines (PC), phosphatidylethanolamines (PE) and phosphatidylserines (PS), and DHA is relatively more concentrated in PE than PC. Naked mole-rats have fewer molecular species of both PC and PE than do mice. DHA-containing phospholipids represent 27-57% of all phospholipids in mice but only 2-6% in naked mole-rats. Furthermore, while mice have small amounts of di-polyunsaturated PC and PE, these are lacking in naked mole-rats. Vinyl ether-linked phospholipids (plasmalogens) are higher in naked mole-rat tissues than in mice. The lower level of DHA-containing phospholipids suggests a lower susceptibility to peroxidative damage in membranes of naked mole-rats compared to mice. Whereas the high level of plasmalogens might enhance membrane antioxidant protection in naked mole-rats compared to mice. Both characteristics possibly contribute to the exceptional longevity of naked mole-rats and may indicate a special role for peroxisomes in this extended longevity."

- Membrane phospholipid composition may contribute to exceptional longevity of the naked mole-rat (Heterocephalus glaber): a comparative study using shotgun lipidomics - PubMed

 

[dhtsupreme]

Sorry, I don't provide personal advice. When was the last time you searched the forum for schizophrenia? I just did a post on that topic a few days ago.

Dopaminergic/antiserotonin drug treats schizophrenia - psychiatry is a giant FRAUD!

Some people make take issue with the title and claim that it is too dramatic. In this case, at least, the title may even be an understatement in regards to evidence of just how utterly FRAUDULENT psychiatry is and has been for decades. Speaking of the latter, psychiatry has claimed for decades...

raypeatforum.com

Ah okay I understand. Thanks anyway.

I saw that post before. Will look into it more. Also will create a post I will include you in. It will include many herbs in a study that have antipsychotic properties.

 

[Regina]

Something that is worth adding to the reasons why naked male rats live so long, is that they have different cell membrane saturation levels than regular rats: they have lower levels of PUFA (espcecially DHA) and higher levels of plasmalogen, which is an endogenous molecule that prevents peroxidative damage. So they are protected twice from PUFA. And the evidence is pretty clear that, the lower the saturation index of an animal ,the longer is their lifespan.

"Phospholipids containing highly polyunsaturated fatty acids are particularly prone to peroxidation and membrane composition may therefore influence longevity. Phospholipid molecules, in particular those containing docosahexaenoic acid (DHA), from the skeletal muscle, heart, liver and liver mitochondria were identified and quantified using mass-spectrometry shotgun lipidomics in two similar-sized rodents that show an approximately 9-fold difference in maximum lifespan. The naked mole rat is the longest-living rodent known with a maximum lifespan of >28 years. Total phospholipid distribution is similar in tissues of both species; DHA is only found in phosphatidylcholines (PC), phosphatidylethanolamines (PE) and phosphatidylserines (PS), and DHA is relatively more concentrated in PE than PC. Naked mole-rats have fewer molecular species of both PC and PE than do mice. DHA-containing phospholipids represent 27-57% of all phospholipids in mice but only 2-6% in naked mole-rats. Furthermore, while mice have small amounts of di-polyunsaturated PC and PE, these are lacking in naked mole-rats. Vinyl ether-linked phospholipids (plasmalogens) are higher in naked mole-rat tissues than in mice. The lower level of DHA-containing phospholipids suggests a lower susceptibility to peroxidative damage in membranes of naked mole-rats compared to mice. Whereas the high level of plasmalogens might enhance membrane antioxidant protection in naked mole-rats compared to mice. Both characteristics possibly contribute to the exceptional longevity of naked mole-rats and may indicate a special role for peroxisomes in this extended longevity."

- Membrane phospholipid composition may contribute to exceptional longevity of the naked mole-rat (Heterocephalus glaber): a comparative study using shotgun lipidomics - PubMed

how cool.

 

[Morten]

The naked mole rat (NMR) is one of the most fascinating species. Despite being a humble rodent, much smaller than a regular house/city rat, the NMR has an exceptionally long life-span of 35+ years (compared to 2-3 years for the common rat) and on top of that is remarkably resistant to the effects of aging - i.e. NMR even in their 30s remain very active, fertile and youthful, without any of the chronic diseases affecting the common rat (e.g. cancer, infections, vascular disease, etc). In other words, not only does the NMR live long, it stays biologically young and highly functional for the vast majority of its lifespan. As such, the NMR has been subjected to numerous studies trying to unravel the secrets of its longevity and health. Unfortunately, most such studies try to come up with genetic explanations, despite complete lack of evidence implicating genes. A much simpler explanation for the exception NMR longevity may be the fact that those rodents live in deep burrows that they almost never leave, and as such are chronically exposed to CO2 ambient concentrations that are many-fold higher than the CO2 exposure of the common rat. One of the results of breathing high-CO2 air is increased uptake and degradation of serotonin (5-HT). Aside from 5-HT having a known role in chronic diseases, the study below now demonstrates that 5-HT may also have a crucial role in aging - i.e. it is the uniquely upregulated degradation of 5-HT in the NMR that prevents the accumulation of senescent (old) cells, thus largely preventing the "old" phenotype in these animals regardless of their age. Aside from increasing endogenous CO2 levels, other interventions that may achieve the same effect in humans is intake of substances known to upregulate the activity of the monoamine-oxidase type A (MAO-A) enzyme discussed in the study. Such substances are vitamin B2 (riboflavin), copper, magnesium, progesterone, and androgens. Obviously, reducing 5-HT synthesis is probably an even better approach, and can be achieved by avoiding dietary tryptophan and/or inhibiting its absorption from the GI tract. Gelatin and aspirin are probably the most appropriate interventions for addressing the tryptophan angle.

https://dx.doi.org/10.15252/embj.2022111133
Japanese scientists may have unraveled the secret of aging resistance in naked mole-rats

"...Naked mole-rats have the longest life span among all rodents and can resist aging and the age-related diseases. However, the precise mechanisms underlying this ability are largely unclear. In a new study, Japanese researchers have identified a unique species-specific "natural senolytic" or senescent cell-removal mechanism in NMRs, involving serotonin metabolism and the INK4a-RB signaling axis. Their findings provide useful insights into ways to resist aging and age-related diseases, including cancer. The study is published in The EMBO Journal. Heterocephalus glaber or naked mole-rats (NMRs)—a mammal species native to Eastern Africa—are the longest-living rodents with an exceptionally long lifespan of over 37 years with a unique ability to delay aging and resist age-related diseases, such as cancer. For these reasons, NMRs have attracted a lot of attention, with researchers hoping to unravel the mechanisms contributing to their longevity."

"...The Department of Aging and Longevity Research, Kumamoto University is the only center in Japan which breeds NMRs and conducts research on their resistance to aging and cancer. Explaining the rationale behind their study, Professor Miura, states, "Senolysis or the targeted removal of senescent cells has been shown to inhibit aging-related decline in mice.""

"...They observed that induction of cellular senescence led to cessation of cell proliferation due to arrest of the cell cycle with the activation of INK4a and RB (important factors for induction of cellular senescence), in both NMR- and mouse-fibroblasts. However, only NMR cells gradually and significantly activated cell death, suggesting that senescent cell accumulation in NMRs may be suppressed through their removal. Through further experiments, the researchers observed that there was an accumulation of serotonin (a neurotransmitter that sends signals between nerve cells) in the non-senescent NMR-fibroblasts, but not in the mouse-fibroblasts. Upon senescence induction, in NMR cells, serotonin was metabolized by monoamine oxidase (MAO; an enzyme highly activated in senescent NMR fibroblasts after induction of cellular senescence) and converted to 5-hydroxyindole acetic acid (5-HIAA; a metabolite), releasing large amounts of hydrogen peroxide (H2O2). The team proposed that oxidative stress due to the intracellular production of H2O2 predisposed the senescent NMR fibroblasts to the cell death pathway, thus leading to senolysis (selective removal of senescent cells). This was confirmed by the observation that the addition of MAO inhibitors and antioxidants inhibited cell death in NMR fibroblasts."

"...Furthermore, treatment with the MAO inhibitor significantly suppressed cell death but increased the number of senescent cells only in NMR lung on day 21. This suggests that MAO plays a role in inducing cell death and reducing the number of senescent cells following the induction of cellular senescence in NMR lung cells. These results are consistent with the in vitro findings and suggest that MAO contributes to suppress the accumulation of senescent cells in NMR tissues."

Gelatin can be "translated" to bonebroth? Is it the high glycine content in broth you refer to?

 

[haidut]

Something that is worth adding to the reasons why naked male rats live so long, is that they have different cell membrane saturation levels than regular rats: they have lower levels of PUFA (espcecially DHA) and higher levels of plasmalogen, which is an endogenous molecule that prevents peroxidative damage. So they are protected twice from PUFA. And the evidence is pretty clear that, the lower the saturation index of an animal ,the longer is their lifespan.

"Phospholipids containing highly polyunsaturated fatty acids are particularly prone to peroxidation and membrane composition may therefore influence longevity. Phospholipid molecules, in particular those containing docosahexaenoic acid (DHA), from the skeletal muscle, heart, liver and liver mitochondria were identified and quantified using mass-spectrometry shotgun lipidomics in two similar-sized rodents that show an approximately 9-fold difference in maximum lifespan. The naked mole rat is the longest-living rodent known with a maximum lifespan of >28 years. Total phospholipid distribution is similar in tissues of both species; DHA is only found in phosphatidylcholines (PC), phosphatidylethanolamines (PE) and phosphatidylserines (PS), and DHA is relatively more concentrated in PE than PC. Naked mole-rats have fewer molecular species of both PC and PE than do mice. DHA-containing phospholipids represent 27-57% of all phospholipids in mice but only 2-6% in naked mole-rats. Furthermore, while mice have small amounts of di-polyunsaturated PC and PE, these are lacking in naked mole-rats. Vinyl ether-linked phospholipids (plasmalogens) are higher in naked mole-rat tissues than in mice. The lower level of DHA-containing phospholipids suggests a lower susceptibility to peroxidative damage in membranes of naked mole-rats compared to mice. Whereas the high level of plasmalogens might enhance membrane antioxidant protection in naked mole-rats compared to mice. Both characteristics possibly contribute to the exceptional longevity of naked mole-rats and may indicate a special role for peroxisomes in this extended longevity."

- Membrane phospholipid composition may contribute to exceptional longevity of the naked mole-rat (Heterocephalus glaber): a comparative study using shotgun lipidomics - PubMed

Great point and study. Thanks for sharing. Yet another confirmation that having low PUFA in cells is beneficial. Ray also mentioned a study showing feeding hydrogenated oil to rats restored their mitochondrial function almost to youthful levels.

Dietary supplementation of old rats with hydrogenated peanut oil restores activities of mitochondrial respiratory complexes in skeletal muscles - PubMed

The effect of dietary supplementation of old rats (26-33 months) with hydrogenated peanut oil on the activity of mitochondrial enzymes in skeletal muscles has been studied. The activities of NADH-coenzyme Q1 oxidoreductase, cytochrome c oxidase, and citrate synthase were determined...

pubmed.ncbi.nlm.nih.gov

And another recent one showed that post-exercise rebound weight gain is also driven by increased unsaturation, leading to lower resting metabolic rate.

Regaining weight post diet/exercise due to lowered metabolism by increased PUFA in cardiolipin

This is by far the most significant study I have seen come out in the last 2-3 years, simply because of the impact it has on virtually every person out there who has tried to lose excess weight (and who hasn't?). Virtually every person considering (or having done) dieting/exercise to lose excess...

raypeatforum.com

Finally, some saturated fats are serotonin antagonists, which would be another pathway through which the naked mole rat keeps serotonin signalling low, even if MAO function declines with age.

 

[learnedhelpless]

Finally, some saturated fats are serotonin antagonists, which would be another pathway through which the naked mole rat keeps serotonin signalling low, even if MAO function declines with age.

Would some types of polyunsaturated fats be serotonin agonists?

 

[Highserotonin90]

@haidut Have you ever discussed the theory of vitamin A toxicity? I would really like to read your thoughts on this. Thank you.

 

[haidut]

Would some types of polyunsaturated fats be serotonin agonists?

I have not looked into that but they are estrogenic and activate the enzyme tryptophan hydroxylase, which synthesizes serotonin.

 

[mostlylurking]

Off topic but still related to serotonin. I wanted to ask what would you do if you had auditory hallucinations? I've read every schizophrenia post and it looks like you'd target serotonin, nitric oxide, and ammonia. Is there anything else you would focus on? What would you take if you had it? Curious @haidut

Auditory hallucinations can be a symptom of thiamine deficiency.

Wernicke’s Encephalopathy Mimicking an Acute Psychotic Disorder

neuro.psychiatryonline.org

[A case of thiamine deficiency with psychotic symptoms--blood concentration of thiamine and response to therapy] - PubMed

We report the case of a 63-year-old woman with thiamine deficiency who showed auditory hallucinations, a delusion of persecution, catatonic stupor, and catalepsy but no neurological symptoms including oculomotor or gait disturbance. Brain MRI did not show high-intensity T2 signals in regions...

pubmed.ncbi.nlm.nih.gov

Please note that thiamine is required to clear serotonin from the brain. Therefore, a thiamine deficiency would result in high serotonin in the brain.

Effect of thiamine deficiency on brain serotonin turnover - PubMed

Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in...

pubmed.ncbi.nlm.nih.gov

Serotonin Syndrome and Thiamine: Is There a Connection? - Hormones Matter

A mild deficiency of thiamine is responsible for the large number of the polysymptomatic illnesses reported.

www.hormonesmatter.com

Thiamine and nitric oxide:

The impact of oxidative stress in thiamine deficiency: A multifactorial targeting issue

Thiamine (vitamin B1) deficiency, the underlying cause of Wernicke–Korsakoff syndrome, is associated with the development of focal neuronal loss in vu…

www.sciencedirect.com

-paste-

Pathophysiology of thiamine deficiency​

The pathophysiological mechanisms involved in TD are complex. Four major enzyme systems utilize thiamine in the form of thiamine diphosphate (TDP) as a major cofactor, i.e. pyruvate dehydrogenase (EC 1.2.4.1) complex (PDHC), an organized enzyme assembly that connects glycolysis with the tricarboxylic acid (TCA) cycle, α-ketoglutarate dehydrogenase (EC 1.2.4.2) complex (KGDHC), a multicomponent enzyme complex associated with the TCA cycle, transketolase (EC 2.2.1.1) (TK), a key participant in

Oxidative stress and excitotoxicity in TD​

Considerable evidence for development of oxidative stress has been demonstrated in TD, including the presence of increased production of reactive oxygen species (ROS) (Langlais and Zhang, 1997), and increased expression of heme oxygenase (HO-1) and intercellular adhesion molecule-1 (ICAM-1) (Gibson and Zhang, 2002) as well as microglial activation (Todd and Butterworth, 1999), along with induction of the endothelial isoform of nitric oxide synthase (eNOS) (Hazell and Butterworth, 2009).

Oxidative stress and inflammatory processes​

Neuroinflammation is now recognized as a key component of a variety of neurological diseases that include stroke, multiple sclerosis and Alzheimer’s disease (AD), along with other problems of the brain such as brain trauma. During the 1960s, alterations in glial cell morphology in TD including evidence of swelling and the appearance of phagocytic vacuoles (Collins, 1967, Robertson et al., 1968) were first reported. These findings are consistent with pathological changes that can be attributable....
-end paste-

Thiamine and ammonia:

[Acute encephalopathy due to thiamine deficiency with hyperammonemia in a chronic hemodialysis patient: a case report] - PubMed

Hemodialysis(HD) patients are at risk for thiamine deficiency because of low intake and accelerated loss of thiamine during HD. We report here an HD patient, an 82-year-old woman, who developed acute encephalopathy due to thiamine deficiency with hyperammonemia. She was admitted to Nishikawa...

pubmed.ncbi.nlm.nih.gov

Hemodialysis(HD) patients are at risk for thiamine deficiency because of low intake and accelerated loss of thiamine during HD. We report here an HD patient, an 82-year-old woman, who developed acute encephalopathy due to thiamine deficiency with hyperammonemia. She was admitted to Nishikawa Town Hospital due to pneumonia and was treated with ABPC/SBT for one week. While she was cured of pneumonia, she had a persistently poor appetite. On the twenty-fourth day after admission, HD with intradialytic parenteral nutrition(IDPN), which consisted of 10% glucose 500 ml, in order to correct her malnutrition, was started. She suddenly presented confusion, speech disturbance and ophthalmoplegia. HD with IDPN was stopped after two hours because of her symptoms. Laboratory studies disclosed plasma glucose of 186 mg/dl and serum ammonium of 155 micrograms/dl. Arterial blood gas analysis(inhaling 3 l/min O2) showed severe metabolic acidosis and respiratory acidosis (pH 7.138, pCO2 44.8 mmHg, pO2 108.9 mmHg, HCO3- 15.1 mmol/l). Her malnutrition, unexplained metabolic acidosis and neurological presentation raised the suspicion of acute encephalopathy due to thiamine deficiency. Fursultiamine 100 mg was administered intravenously. After two hours, metabolic acidosis disappeared (pH 7.437, pCO2 33.9 mmHg, pO2 161.0 mmHg, HCO3- 22.9 mmol/l), and she regained her clear consciousness and serum ammonium decreased at 16 micrograms/dl on the next morning. Serum lactate and thiamine level were shown later to be 57.5 mg/dl and 27 nmol/l, respectively. Her clinical course suggests that the glucose load including IDPN may have caused deterioration of the neurological disorder under the condition of thiamine deficiency. Furthermore, it is possible that a relationship exists between thiamine deficiency and hyperammonemia.

THIAMINE DEFICIENCY AND HEPATIC ENCEPHALOPATHY IN A CIRRHOTIC PATIENT; CO-MORBID CONDITIONS THAT ARE OFTEN UNRECOGNIZED? - SHM Abstracts | Society of Hospital Medicine

Case Presentation: 74-year-old male with history of NASH cirrhosis with Grade I esophageal variceal bleeding history, SDH s/p burr hole drainage with course complicated by seizures on Keppra and Vimpat, type 2 diabetes mellitus, and coronary artery disease status post 1 drug eluting stent who...

shmabstracts.org

-paste-
"Co-administering thiamine supplementation and ammonia reducing agents, regardless of the etiology of liver failure, has a synergistic effect in the treatment HE (Hepatic encephalopathy). Prompt thiamine supplementation should be considered in all patients with HE from end stage liver disease, especially when they do not adequately respond to standard ammonia lowering agents."

 

[mostlylurking]

Would some types of polyunsaturated fats be serotonin agonists?

I think that all polyunsaturated fats (PUFA) would be serotonin agonists, at least brain serotonin, because PUFA depletes thiamine and thiamine is required to remove serotonin from the brain.

PUFA depletes thiamine:

Changes in thiamine concentrations, fatty acid composition, and some other lipid-related biochemical indices in Baltic Sea Atlantic salmon (Salmo salar) during the spawning run and pre-spawning fasting - Helgoland Marine Research

Salmonines in the Baltic Sea and North American lakes suffer from thiamine (vitamin B1) deficiency, which is connected to an abundant lipid-rich diet containing substantial amounts of polyunsaturated fatty acids (PUFAs). In the Baltic region, this is known as the M74 syndrome. It affects both...

hmr.biomedcentral.com

"Salmonines in the Baltic Sea and North American lakes suffer from thiamine (vitamin B1) deficiency, which is connected to an abundant lipid-rich diet containing substantial amounts of polyunsaturated fatty acids (PUFAs)." (Evidently, fish oil isn't even good for the fish.)

thiamine reduces serotonin in the brain:

Effect of thiamine deficiency on brain serotonin turnover - PubMed

Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in...

pubmed.ncbi.nlm.nih.gov

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Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in the medulla-pons, hypothalamus and cerebral cortex. [14C]5-HT levels were normal in all of the brain areas except the cerebral cortex which had an increase of 58%. The ratio of [14C]5-HIAA/[14C]5-HT was significantly increased in every brain region of PT-treated rats except the cerebral cortex. Part of this increase in [14C]5-HIAA was shown to be due to impairment of active transport of this 5-HT metabolite out of the brain. However, increased 5-HT synthesis in the cerebellum, hypothalamus, striatum, hippocampus and cerebral cortex was demonstrated by measurement of 5-HT accumulation after inhibition of brain monoamine oxidase. PT-induced increase in endogenous 5-HIAA in the medulla-pons occurred simultaneously with the onset of neurological signs and both parameters were reversible by thiamine administration. These results suggest that acute thiamine deficiency, induced by PT, both increases brain 5-HT synthesis and impairs 5-HIAA efflux from the brain. There is a close correlation between neurological manifestations and changes in brain 5-HT metabolism in acute thiamine deficiency.

 

[dhtsupreme]

Auditory hallucinations can be a symptom of thiamine deficiency.

Wernicke’s Encephalopathy Mimicking an Acute Psychotic Disorder

neuro.psychiatryonline.org

[A case of thiamine deficiency with psychotic symptoms--blood concentration of thiamine and response to therapy] - PubMed

We report the case of a 63-year-old woman with thiamine deficiency who showed auditory hallucinations, a delusion of persecution, catatonic stupor, and catalepsy but no neurological symptoms including oculomotor or gait disturbance. Brain MRI did not show high-intensity T2 signals in regions...

pubmed.ncbi.nlm.nih.gov

Please note that thiamine is required to clear serotonin from the brain. Therefore, a thiamine deficiency would result in high serotonin in the brain.

Effect of thiamine deficiency on brain serotonin turnover - PubMed

Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in...

pubmed.ncbi.nlm.nih.gov

Serotonin Syndrome and Thiamine: Is There a Connection? - Hormones Matter

A mild deficiency of thiamine is responsible for the large number of the polysymptomatic illnesses reported.

www.hormonesmatter.com

Thiamine and nitric oxide:

The impact of oxidative stress in thiamine deficiency: A multifactorial targeting issue

Thiamine (vitamin B1) deficiency, the underlying cause of Wernicke–Korsakoff syndrome, is associated with the development of focal neuronal loss in vu…

www.sciencedirect.com

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Pathophysiology of thiamine deficiency​

The pathophysiological mechanisms involved in TD are complex. Four major enzyme systems utilize thiamine in the form of thiamine diphosphate (TDP) as a major cofactor, i.e. pyruvate dehydrogenase (EC 1.2.4.1) complex (PDHC), an organized enzyme assembly that connects glycolysis with the tricarboxylic acid (TCA) cycle, α-ketoglutarate dehydrogenase (EC 1.2.4.2) complex (KGDHC), a multicomponent enzyme complex associated with the TCA cycle, transketolase (EC 2.2.1.1) (TK), a key participant in

Oxidative stress and excitotoxicity in TD​

Considerable evidence for development of oxidative stress has been demonstrated in TD, including the presence of increased production of reactive oxygen species (ROS) (Langlais and Zhang, 1997), and increased expression of heme oxygenase (HO-1) and intercellular adhesion molecule-1 (ICAM-1) (Gibson and Zhang, 2002) as well as microglial activation (Todd and Butterworth, 1999), along with induction of the endothelial isoform of nitric oxide synthase (eNOS) (Hazell and Butterworth, 2009).

Oxidative stress and inflammatory processes​

Neuroinflammation is now recognized as a key component of a variety of neurological diseases that include stroke, multiple sclerosis and Alzheimer’s disease (AD), along with other problems of the brain such as brain trauma. During the 1960s, alterations in glial cell morphology in TD including evidence of swelling and the appearance of phagocytic vacuoles (Collins, 1967, Robertson et al., 1968) were first reported. These findings are consistent with pathological changes that can be attributable....
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Thiamine and ammonia:

[Acute encephalopathy due to thiamine deficiency with hyperammonemia in a chronic hemodialysis patient: a case report] - PubMed

Hemodialysis(HD) patients are at risk for thiamine deficiency because of low intake and accelerated loss of thiamine during HD. We report here an HD patient, an 82-year-old woman, who developed acute encephalopathy due to thiamine deficiency with hyperammonemia. She was admitted to Nishikawa...

pubmed.ncbi.nlm.nih.gov

Hemodialysis(HD) patients are at risk for thiamine deficiency because of low intake and accelerated loss of thiamine during HD. We report here an HD patient, an 82-year-old woman, who developed acute encephalopathy due to thiamine deficiency with hyperammonemia. She was admitted to Nishikawa Town Hospital due to pneumonia and was treated with ABPC/SBT for one week. While she was cured of pneumonia, she had a persistently poor appetite. On the twenty-fourth day after admission, HD with intradialytic parenteral nutrition(IDPN), which consisted of 10% glucose 500 ml, in order to correct her malnutrition, was started. She suddenly presented confusion, speech disturbance and ophthalmoplegia. HD with IDPN was stopped after two hours because of her symptoms. Laboratory studies disclosed plasma glucose of 186 mg/dl and serum ammonium of 155 micrograms/dl. Arterial blood gas analysis(inhaling 3 l/min O2) showed severe metabolic acidosis and respiratory acidosis (pH 7.138, pCO2 44.8 mmHg, pO2 108.9 mmHg, HCO3- 15.1 mmol/l). Her malnutrition, unexplained metabolic acidosis and neurological presentation raised the suspicion of acute encephalopathy due to thiamine deficiency. Fursultiamine 100 mg was administered intravenously. After two hours, metabolic acidosis disappeared (pH 7.437, pCO2 33.9 mmHg, pO2 161.0 mmHg, HCO3- 22.9 mmol/l), and she regained her clear consciousness and serum ammonium decreased at 16 micrograms/dl on the next morning. Serum lactate and thiamine level were shown later to be 57.5 mg/dl and 27 nmol/l, respectively. Her clinical course suggests that the glucose load including IDPN may have caused deterioration of the neurological disorder under the condition of thiamine deficiency. Furthermore, it is possible that a relationship exists between thiamine deficiency and hyperammonemia.

THIAMINE DEFICIENCY AND HEPATIC ENCEPHALOPATHY IN A CIRRHOTIC PATIENT; CO-MORBID CONDITIONS THAT ARE OFTEN UNRECOGNIZED? - SHM Abstracts | Society of Hospital Medicine

Case Presentation: 74-year-old male with history of NASH cirrhosis with Grade I esophageal variceal bleeding history, SDH s/p burr hole drainage with course complicated by seizures on Keppra and Vimpat, type 2 diabetes mellitus, and coronary artery disease status post 1 drug eluting stent who...

shmabstracts.org

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"Co-administering thiamine supplementation and ammonia reducing agents, regardless of the etiology of liver failure, has a synergistic effect in the treatment HE (Hepatic encephalopathy). Prompt thiamine supplementation should be considered in all patients with HE from end stage liver disease, especially when they do not adequately respond to standard ammonia lowering agents."

Very interesting. I wish my problem was a thiamine deficiency. I know it's more complex since I take a B complex and use energin. I still have it and it's difficult to live with. Thanks for sharing

I included you in a different post about auditory hallucinations. It includes a question about high dopamine in the mesolimbic area and low levels in the mesorcortical area causing positive and negative symptoms. Just want your opinion on that theory @haidut

 

[Mauritio]

Great point and study. Thanks for sharing. Yet another confirmation that having low PUFA in cells is beneficial. Ray also mentioned a study showing feeding hydrogenated oil to rats restored their mitochondrial function almost to youthful levels.

Dietary supplementation of old rats with hydrogenated peanut oil restores activities of mitochondrial respiratory complexes in skeletal muscles - PubMed

The effect of dietary supplementation of old rats (26-33 months) with hydrogenated peanut oil on the activity of mitochondrial enzymes in skeletal muscles has been studied. The activities of NADH-coenzyme Q1 oxidoreductase, cytochrome c oxidase, and citrate synthase were determined...

pubmed.ncbi.nlm.nih.gov

And another recent one showed that post-exercise rebound weight gain is also driven by increased unsaturation, leading to lower resting metabolic rate.

Regaining weight post diet/exercise due to lowered metabolism by increased PUFA in cardiolipin

This is by far the most significant study I have seen come out in the last 2-3 years, simply because of the impact it has on virtually every person out there who has tried to lose excess weight (and who hasn't?). Virtually every person considering (or having done) dieting/exercise to lose excess...

raypeatforum.com

Finally, some saturated fats are serotonin antagonists, which would be another pathway through which the naked mole rat keeps serotonin signalling low, even if MAO function declines with age.

Interesting study as well.
And the study design wasn't even very good in terms of saturation and amount fed.
The oil they fed was 70% MUFA, so the study migth have been even more successfull if the oil fed was 70% SFA. The amount also seems relatively small to me ("During 6 weeks the rats daily obtained 0.50.7 mlof hydrogenated peanut oil (Fluka, Germany) added to asmall amount of oat flakes boiled with water").

But even a switch from PUFA to MUFA can cause a big difference as seen and there was a another study I posted where they switched subjects from a PUFA to MUFA diet and their MDA level was almost 4 times lower on the MUFA diet.

Here is the study:

In this human study they showed that the level of the major lipid peroxidation product malonaldehyde (MA) was 3,6 times higher in human that ate a diet rich in PUFA compared to humans that ate a MUFA-rich diet .

"The average adduct level in the SO diet group was 7.4 +/- 8.7 adducts/10(7) nucleotides (n = 23). This level was 3.6-fold higher than that found in individuals in the RO diet group (P < 0.001). Our results, in conjunction with the mutagenic and carcinogenic properties of MA, thus suggest the interaction of lipid peroxidation products such as MA with DNA as one plausible mechanism explaining the involvement of dietary fat in carcinogenesis."

Determination of DNA adducts of malonaldehyde in humans: effects of dietary fatty acid composition - PubMed

The effects of dietary fatty acid composition on the endogenous formation of DNA adducts of malonaldehyde (MA), the major product of lipid peroxidation, were investigated in humans. A group of 59 healthy individuals of both sexes and different ages was initially fed a milk fat-based diet rich in...

pubmed.ncbi.nlm.nih.gov

 

[Mauritio]

@haidut Have you ever discussed the theory of vitamin A toxicity? I would really like to read your thoughts on this. Thank you.

yes he discussed it on Danny's podcast. use bioenergetic.life to find it.

 

[Mufasa]

Through further experiments, the researchers observed that there was an accumulation of serotonin (a neurotransmitter that sends signals between nerve cells) in the non-senescent NMR-fibroblasts, but not in the mouse-fibroblasts.

But why is there an accumulation of serotonin in non-senescent NMR-fibroblasts, and not in the mouse-fibroblasts.
Wouldn't you expect that serotonin is low in NMR cells instead?

Also, the study says that NMR cells have a unique low mitochondrial activity:

NMR cells have low mitochondrial activity, a low oxygen consumption rate, and high mitochondrial ROS scavenging activity (Munro et al, 2019; Lau et al, 2020). Therefore, their vulnerability to intracellular H2O2 may not be a concern because ROS leakage from mitochondria is low in the normal state. Until now, the biological significance of the vulnerability of NMR cells to H2O2 remained unclear. The present results suggest that this vulnerability likely contributes to INK4a-RB cell death in conjunction with the unique regulation of serotonin metabolic switch, which produces H2O2 when NMR cells become senescent.

So to me it seems more that the study tries to say that NRM rats have a unique low metabolism, accumulate serotonin, and that on senescence, the cells upregulate MOA, to use this "serotonin" reservoir to kill themselves by producing a lot of H202.