New study says increased circulating levels of O6 PUFA arachidonic acid is fasting's mechanism for lowering inflammation (30 Jan 2024)
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Scientists identify how fasting may protect against inflammation
30 Jan 2024
https://www.cam.ac.uk/research/news/scientists-identify-how-fasting-may-protect-against-inflammationThe team found that restricting calorie intake increased levels of a lipid known as arachidonic acid. Lipids are molecules that play important roles in our bodies, such as storing energy and transmitting information between cells. As soon as individuals ate a meal again, levels of arachidonic acid dropped.
When the researchers studied arachidonic acid’s effect in immune cells cultured in the lab, they found that it turns down the activity of the NLRP3 inflammasome. This surprised the team as arachidonic acid was previously thought to be linked with increased levels of inflammation, not decreased.
........................................................................................................................................................................................................Unsatured O6 PUFA is bad or it's the mechanism for lowering inflammation
. Arachidonic acid is the worst of them, the boogeyman of fatty acids. -
the actual study:
Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting
https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00028-7
Highlights
•In fasting compared to fed subjects, plasma IL-1β is lower and arachidonic acid (AA) is higher
•Exogenous AA impairs NLRP3 inflammasome activity in human and mouse macrophages
•AA inhibits phospholipase C and reduces JNK stimulation and hence NLRP3 activitySummary
Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work. -
Hi,
Thanks for posting but I won’t take these studies for granted findings. Deductions are no valid arguments, for me, here. Why?
Main points in the first study:- AA reduces inflammasones (it turns down the activity of the NLRP3 inflammasome in cell culture and in mouse).
- We already know fasting improves brain biology. Of course if we fast 24 H after a meal of 500 K/cal, it will induce lipogenesis, and thus fat that has been stored, often AA, supposed to be pro-inflammatory because training a cascade reaction. We make a statement but we don’t know how or why in some ways.
But we know too that very long PUFAs depress the system and the thyroid if prolonged.
The only interesting thing in this first study is the conclusion, not oriented: - “There could be a yin and yang effect going on here, whereby too much of the wrong thing is increasing your inflammasome activity and too little is decreasing it,” said Professor Bryant. “Arachidonic acid could be one way in which this is happening.”
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@LucH said in New study says increased circulating levels of O6 PUFA arachidonic acid is fasting's mechanism for lowering inflammation (30 Jan 2024):
Thanks for posting but I won’t take these studies for granted findings. Deductions are no valid arguments, for me, here.
I agree. Unfortunately it takes a great deal of time and sophistication to estimate the quality of a study and usefulness of the data. I'm just throwing it out there. I came upon it researching something unrelated.
I believe they're suggesting nsaids like aspirin actually preserve arachidonic acid by not letting it convert:
"Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production." -
@Insomniac said in New study says increased circulating levels of O6 PUFA arachidonic acid is fasting's mechanism for lowering inflammation (30 Jan 2024):
I believe they're suggesting nsaids like aspirin actually preserve arachidonic acid by not letting it convert:
"Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production."Well said / pointed.
Here is what I found on the process of acetyl salicylic.I remind having read aspirin has a dual effect on COX1-2 according to the dose. So, on COX-2 as well, even if weaker. And by the way, whenever one way is blocked by NSAID (PGE2), another one way will rise if it lasts too long.
Thus more selective for Cox1 than Cox2, yes. A common hypothesis states that selective COX-2 inhibitors might be pro-thrombotic by inhibiting prostacyclin formation while leaving COX-1 induced thromboxane formation unopposed, in this way disturbing the balance between suppression and promotion of aggregation [26].Excerpt 1:
Acetylsalicylic acid has been reported to be an irreversible inhibitor of COX: it inactivates platelet COX-1 irreversibly by acetylating a single serine residue in the enzyme [35]. This indicates that new synthesis of the enzyme is needed to reactivate prostanoid production. Because platelets are not able to synthesize COX, aspirin blocks the activity of this enzyme for the life-time of the cell [36]. In the present study, after a single oral dose (500 mg), acetylsalicylic acid did not have any significant effect on COX-2 activity ex vivo, and thus appears to be COX-1-selective.
Excerpt 2:
Aspirin imparts its antiplatelet activity by irreversibly acetylating COX-1, leading to inhibition of platelet thromboxane (TX) A2 formation (1, 7). In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, aspirin restricts access of arachidonic acid (AA) to the COX catalytic core by covalently modifying a serine residue near the active site of the enzyme (1, 7)
doi: 10.1073/pnas.1933204100 2003The hypothesis that COX-2 inhibition increases platelet aggregability also in humans seems to be contradicted by clinical and laboratory studies [8-15].
doi: 10.2174/1874192401004010198 2010
(…) This suggests that inhibition of COX-2 in healthy man is of limited risk. In cardiovascular patients, however, COX-2 inhibition might amplify aggregation elicited by e.g. rupture of an atherosclerotic plaque or further narrowing of a vascular stenosis.Low-dose Aspirin Goes Beyond COX-1: Exciting New Mechanistic Insights Into Cancer Prevention
AACR. October 1, 2014 by Srivani Ravoori, PhD.
https://www.aacr.org/blog/2014/10/01/low-dose-aspirin-goes-beyond-cox-1/
Low-dose aspirin via inhibition of the COX-1 pathway may play a role in lowering the risk for many different cancers.
“We found that the potency of low-dose aspirin (81 mg) in inhibiting COX-2 in the tumor cells is as great or greater than its potency as an inhibitor of COX-1 in the platelet,” said Pierre Massion, MD. Activated platelets are known to facilitate the movement of tumor cells, and therefore, metastasis. So, Massion and his team speculate that the antiplatelet and COX-2 inhibitory activities of low-dose aspirin may act in concert to lower the risk for cancer metastasis and mortality.
Massion and colleagues found that the doses of aspirin needed to inhibit COX-2-mediated PGE2 production was up to 12 times lower than the dose needed to exert its COX-1-mediated antiplatelet effects, when tested in three lung adenocarcinoma cell lines.Aspirin – Mecanism of Action
https://www.ahajournals.org/doi/10.1161/01.cir.101.10.1206
https://doi.org/10.1161/01.CIR.101.10.120
Aspirin imparts its primary antithrombotic effects through the inhibition of PGH-synthase/COX by the irreversible acetylation of a specific serine moiety (serine 530 of COX-1 and serine 516 of COX-2)11 12 and is ≈170-fold more potent in inhibiting COX-1 than COX-2.13 In the presence of aspirin, COX-1 is completely inactivated, whereas COX-2 converts arachidonic acid not to PGH2, but to 15-R-hydroxyeicosatetraenoic acid (15-R-HETE). 14 The end result is that neither affected isoform is capable of converting arachidonic acid to PGH2, a necessary step in the production of prostanoids. The resultant decreased production of prostaglandins and TXA2 likely accounts for the therapeutic effects, as well as the toxicities, of aspirin. From a cardiovascular standpoint, it is principally the antithrombotic effect of aspirin that results in its clinical utility. Platelet production of TXA2 in response to a variety of stimuli (including collagen, thrombin, and ADP) results in the amplification of the platelet aggregation response and in vasoconstriction.15 16 -
Massion and colleagues found that the doses of aspirin needed to inhibit COX-2-mediated PGE2 production was up to 12 times lower than the dose needed to exert its COX-1-mediated antiplatelet effects, when tested in three lung adenocarcinoma cell lines.
Aspirin – Mecanism of Action
https://www.ahajournals.org/doi/10.1161/01.cir.101.10.1206
https://doi.org/10.1161/01.CIR.101.10.120
Aspirin imparts its primary antithrombotic effects through the inhibition of PGH-synthase/COX by the irreversible acetylation of a specific serine moiety (serine 530 of COX-1 and serine 516 of COX-2)11 12 andis ≈170-fold more potent in inhibiting COX-1 than COX-2.Nice follow up. Fascinating stuff.
Which is it?
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@LucH said in New study says increased circulating levels of O6 PUFA arachidonic acid is fasting's mechanism for lowering inflammation (30 Jan 2024):
Hi,
Thanks for posting but I won’t take these studies for granted findings. Deductions are no valid arguments, for me, here. Why?
Main points in the first study:- AA reduces inflammasones (it turns down the activity of the NLRP3 inflammasome in cell culture and in mouse).
- We already know fasting improves brain biology. Of course if we fast 24 H after a meal of 500 K/cal, it will induce lipogenesis, and thus fat that has been stored, often AA, supposed to be pro-inflammatory because training a cascade reaction. We make a statement but we don’t know how or why in some ways.
But we know too that very long PUFAs depress the system and the thyroid if prolonged.
The only interesting thing in this first study is the conclusion, not oriented: - “There could be a yin and yang effect going on here, whereby too much of the wrong thing is increasing your inflammasome activity and too little is decreasing it,” said Professor Bryant. “Arachidonic acid could be one way in which this is happening.”
You can basically abolish the “brain improvements” of fasting just by consuming tryptophan, even if you don't consume anything else.
We found that adding back carbohydrate or fat did not affect Dietary Restricted(DR)-induced memory retention of mice in the NOR test (Fig 2A), indicating that these constituents do not limit memory performance during DR. In contrast, addition of protein to the DR diet attenuated DR-induced memory performance, bringing it back to alevel comparable to that for AL mice (Fig 2A). We next determined which amino acid affected memory function in this context....
Our results demonstrated that adding back tryptophan, but not glutamate, cysteine, or tyrosine, attenuated DR-induced memory retention (Fig 2B). Tryptophan alone is thus limiting for memory retention during DR. Although adding back carbohydrate and fat, but not protein or individual amino acids, significantly increased the body weight of DR mice (S2A and S2D Fig), none of these dietary manipulations affected general locomotor activity or total time spent on object exploration, compared to either the AL or DR group in the open field test or NOR test, respectively
I'm not sure what they were trying to see in relation to NSAIDs like aspirin, but they inhibit COX-1/2, for them to decrease the level of AA they would have to inhibit Phospholipase A2, which is the enzyme that releases AA from the membrane to be processed by COXs.
It wouldn't be surprising to see a negative feedback mechanism in relation to AA levels in an isolated variable like the one in this study, and there are other ways in which AA can influence this, after all, an increase in AA means more substrate for other things. I remember Travis commenting on AA influencing PPARδ and it also participates in inflammation, so maybe it's responsible for the negative feedback? haha
These findings indicate that PPARδ agonists have the potential to suppress the inflammatory response that triggers atherosclerosis
Some of Travis' mentions of Phospholipase A2:
Han starts off his article quite appropriately by mentioning phospholipase A₂. This is a real enzyme, and can cleave arachidonic acid from membrane phospholipids in vitro. It cannot do this at low lipid concentrations, but once a micelle is formed it will stick to it and start cleaving. The cell membrane is presumed to be similar to a phospholipid micelle. Phospholipase A₂ can cleave phosphotidylethanolamine, but needs to be anchored to phosphotidylcholine to do so. It will not anchor to an in vitro micelle composed exclusively of phosphotidylethanolamine.
By the way, another thing that Click mentioned in X in relation to a possible anti-inflammatory mechanism of fasting is the very restriction of methionine, which is a component of COX-2. One might expect a reduction in inflammation just by restricting some amino acids, on top of restricting other elements that can contribute.
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By the way.
Ray and Haidut had mentioned in many articles and interviews that PUFAs only temporarily suppress inflammation but do not heal it.
Therefore all such information as research above should be taken in a proper (complex/holistic) context.Peatbot: According to the context provided, polyunsaturated fatty acids (PUFA) can have an anti-inflammatory effect, but this effect is primarily due to their oxidized form, which suppresses the immune system. This suppression can interrupt an existing inflammatory process, but it does not necessarily lead to healing. In fact, prolonged use of PUFA for its anti-inflammatory effects can result in immunodepression, which is a longer-range effect. Therefore, while PUFA may suppress inflammation, they do not necessarily promote healing and can have toxic effects in the long run.
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@TexugoDoMel I was trying to quote the good parts from your post but the whole thing was very useful. Thanks for advancing the subject
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One can bury a bomb and produce the artifice of calm. That bomb will stay go off eventually.
