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St. John's Wort as an anti-aging herb

st. johns wort hyperforin pxr lxr 5-lo cytochrome p450 apoe vitamin d

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#1 timar

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Posted 28 March 2015 - 11:45 AM


I orginally wrote this as a response to this topic but I decided that it steered to far away from it and deverses its own topic.

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St. John's wort has several fascinating properties, making it interesting as a longevity herb. The two most important ones are:

 

1) Hyperforin is an extremely powerful 5-LO inhibitor (IC50 90 nM, about 8 times as potent as curcumine [700 nM])

 

Arachidonate 5-lipoxygenase (5LO) is the enzyme that produces pro-inflammatory leukotrienes from arachidonic acid. Given the emerging role of inflammation in depression and other psychatric disorders, it seems likely that the antidepressive effects of St. John's Wort are not exclusively due to the reuptake inhibition of neurotransmitters, but also due to its potent anti-inflammatory effects. As 5-LO is upregulated in many inflammatory diseases and cancer cell lines, synthetic 5-LO inhibitors are considered a gold mine for future anti-inflammatory and anti-cancer drugs, but far no synthetic inhibitor has been developed as powerful as hyperforin.

 

2) Hyperforin is an extremely powerful PXR activator (EC50 20 nM).

 

The pregnane X receptor (PXR, aka steroid and xenobiotic receptor SXR) is considered the master regulator of xenobiotic metabolism in mammalian physiology. It has a impact on gene expression, strongly upregulating phase I and II detoxification enzymes. Hyperforin is one of the most potent known activators of PXR, even more potent than the prototypical activator, rifampicin. I believe that regularly hitting PXR with low-dose St. John's Wort may excert similar effects as taking large doses of polyphenolic phytochemicals, who induce the xenobiotic response to much lesser degree. A elevated activity in the cytochrome P450 system of enzymes - either genetically or due to lifestyle factors - has been associated with longevity in humans. In hypercholesterolemic rabbits expressing human PXR, St. John's wort extract potently lowered cholesterol, inflammatory biomarkes and prevented the formation of artherosclerosis more potently than lovastatin.

 

I began taking St. John's wort - which is widely available here in Germany and has a long history of use - several years ago to deal with the mood swings I used to experience (possibly related to a sudden drop in serotinin) and found it effective not to completely prevent them but to reduce their frequency and severity. After taking it for a while without experiencing any negative side-effects and becoming more and more familiar with the literature about St. John's wort and nuclear receptors such as PXR, I decided no keep taking a low dose (180 mg extract, providing ~5 mg of hyperforin) as part of my general longevity regime. Given the pharmacokinetics of hyperforin, this dose is low enough not to significantly affect neurotransmitter reuptake, but high enough to excert some 5-LO inhibiting activity and probably to fully acitivate PXR.

 

An important fact to consider is that the PXR is a highly promiscuous receptor, activated not only by a diverse array of xenobiotics but also by endogenous ligands and is closely related to the liver X receptor (LXR), which is expressed more tissue-specifically, activated predominantly by endogenous ligands such as oxysterols, plays a key role in cholesterol homeostasis and shares a large subset of target genes with the PXR.

 

The question of course is: If a high level of PXR activation is beneficial, why hasn't it evolved as the physiological default state? The answer is probably economy. The induction of detoxification enzyes is metabolically costly, consuming vital micronutrients and cofactors. Therefore, in an evolutionary environment where scarcity was the norm, it has proven advantageus to evolve a highly sensitive xenohormetic detector, in order to broadly boost the expression of those enzymes only when needed,

 

There is an important downside of PXR activation though, which has to be mentioned. The expression of cytochrome P450 does not only boost detoxification of oxysterols and other endogenous metabolic waste but also that of some beneficial, including multiple important drugs, such as statins. This is why anyone taking St. John's Wort together with a prescription drug should be carefully examine possible interactions. PXR activation also inhibits the conversion of vitamin D to its prehormone form, 25-hydroxyvitamin D as part of a physiological feeback mechanism, which makes monitoring of 25(OH)D mandatory. However, as I have written before, this is likely the very reason why low levels of vitamin D are genetically associated with longevity and high levels of vitamin D and the same is true the other way around.

 

This observation could further refine the economy hypothesis of PXR/LXR activity. One could speculate that the insufficient biochemical ability of the cytochrome system to differentiate between oxysterols and useful cholesterol metabolites such as vitamin D resulted in a case of antagonistic pleiotropy where trade-off phenotypes such as ApoE3 have been positively selected for. The role of vitamin D in immune function is evolutionary more important than the adverse effects of high cholesterol in old age - so we see a higher distribution of ApoE4 in northern latidutes.

 

Maybe, just maybe, by taking low-dose St. John's wort as well as vitamin D we can overcome this antagonism :)


Edited by timar, 28 March 2015 - 11:52 AM.

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#2 Darryl

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Posted 28 March 2015 - 08:02 PM

Thanks for the heads-up on PXR: xenobiotic metabolism appears to be regulated  by a pretty complicated interplay between aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor α (PPARα), and nuclear factor-E2-related factor 2 (Nrf2), some of which amplify each other via crosstalk.

 

A drug discovery group would be very happy with a EC50 of 20 nM.

 

This paper appears particularly relevant to St. John's Wort and neurodegenerative disease:

 

Kraus, B., Wolff, H., Elstner, E. F., & Heilmann, J. (2010). Hyperforin is a modulator of inducible nitric oxide synthase and phagocytosis in microglia and macrophagesNaunyn-Schmiedeberg's archives of pharmacology381(6), 541-553.


Edited by Darryl, 28 March 2015 - 08:49 PM.

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#3 timar

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Posted 29 March 2015 - 09:14 AM

Thank you for the reference, Darryl, that paper escaped my attention so far. The concentration at which they saw those anti-inflammatory effects seem physiologically relevant and should be attainable with the higher dose range used for depression.

 

Thanks for the heads-up on PXR: xenobiotic metabolism appears to be regulated  by a pretty complicated interplay between aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor α (PPARα), and nuclear factor-E2-related factor 2 (Nrf2), some of which amplify each other via crosstalk.

 

The problem with AhR is that most of its ligands are actually quite toxic (maybe it's possible to regularly reach the EC50 by a diet of burned toast and charrred meat) and when it comes CAR.. well, St. John's wort seems much preferable to phenobarbital ;)

 

Of course Nrf2 is probably the most important aspect of xenobiotic metabolism with regard to longevity so my remark that PXR activation may have "similar effects as taking large doses of polyphenolic phytochemicals" is of course oversimplified and related to the effects on cholesterol homeostasis.

 

Why do we have these two very different, promiscuous pathways? My hypothesis is that while PXR activates the metabolically costly targets, Nrf2 activation actually does the opposite. Let me explain: If you suffer a famine, you want to ramp up autophagy but not let any precious cholesterol go to waste. Why does NRF2 activation, as well as other targets of polyphenols, share so many downstream effects with caloric restiction? Maybe it is simply the denomitator, while protein restriction is the enumerator. During famine, you begin to eat all sorts of unusual low-caloric but phytochemical-rich foods, so the ratio of calories to polyphenols seems a more sensitive predictor of caloric scarcity than calories or protein alone.

 

A drug discovery group would be very happy with a EC50 of 20 nM.

 

Indeed. It is a rare and fascinating opportunity to have a natural, well-tolerated ligand with such potency.

 

Just think of all the RCTs with St. John's wort in depression and psychological disorders. I have looked through them to see if any has reported on between-group differences in cholesterol levels, but unfortunately none of them did. If they drew blood samples, there may be a gold mine left to explore. I wish I knew my own cholesterol levels before I started my St. John's wort regime, but today my LDL is below 100 despite not eating a vegan diet and not really restricting saturated fat.


Edited by timar, 29 March 2015 - 10:01 AM.


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#4 timar

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Posted 29 March 2015 - 11:39 AM

An interesting, recent animal study on the anti-inflammatory and immunomodulatory activities of St. John's wort. Note that "enhancement of foot pad thickness" actually means a significant decrease in foot pad thickness. You definitely notice that English isn't the second language in Iran ;)

 

Avicenna J Phytomed. 2015 Jan-Feb; 5(1): 62–68.
Immunomudulatory [sic] effects of hydroalcoholic extract of Hypericum perforatum
Seyyed Meysam Abtahi Froushani, Hadi Esmaili gouvarchin Galee, Mahsa Khamisabadi, and Bita Lotfallahzade
 

Objective: Hypericum perforatum (St. John's Wort) has long been used in traditional medicine to treat a variety of internal and external ailments. The present study was done to evaluate the immumodulatory potentials of the hydroalcoholic extract of H. perforatum.

Materials and Methods: Twenty male BALB/c-mice were randomly allocated in two equal groups and immunized with sheep red blood cells (SRBCs) and complete Freund’s adjuvant. Mice in the treatment group orally received hydroalcoholic extract of H. perforatum (110 mg/Kg daily) from the beginning of the study which continued for 2 weeks.

Results: The data indicated a significant increase in the level of anti-SRBC antibody and simultaneously a significant decrease in the level of cellular immunity, an enhancement in foot pad thickness, in treatment group compared to control group. The level of the respiratory burst in phagocytic cells and the level of lymphocyte proliferation in splenocytes were significantly decreased in the treatment group compared to control group. Moreover, extract caused a significant reduction in the production of pro-inflammatory IL-17 as well as IFN-γ, parallel to increasing the level of IL-6.

Conclusions: The hydroalcoholic extract of H. perforatum may be used as a natural source for treatment of immunopathologic conditions.

→ source (external link)

 


Edited by timar, 29 March 2015 - 11:51 AM.






Also tagged with one or more of these keywords: st. johns wort, hyperforin, pxr, lxr, 5-lo, cytochrome p450, apoe, vitamin d

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