5 replies to this topic

[elc202]

Hi,

 

18-hydroxyeicosapentaenoic acid (18-HEPE)

17-hydroxydocosahexaenoic acid (17-HDHA)

14-hydroxydocosahexaenoic acid (14-HDHA)

 

I have been seeing several brands selling them in the last 2 years. Very expensive. Thorne sells it for $66.

But this week I noticed that LE is selling it for $11 only. So I'm curious. Specially if they help issues like MS, Recovery After Surgery, and Alzheimer's.

Anyone familiar with them? What was your experience?

 

Thanks,

[ironfistx]

Yup. Kinda.

There are some posts on other forums about this with no responses.

Iirc, life extension contains 2 kinds metagenics contains 3.

Life extension is usually $19 but it been discounted heavily recently.

I've used it.

[CynthesisToday]

There is certainly evidence that _if_ 18-HEPE (etc) get to the brain (or other inflammatory site) they can have positive effect in decreasing inflammation and producing measurable improvement in symptoms. See for example: https://www.nature.c...380-021-01160-8 "Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis" (2021, full paper). This paper demonstrates improvement by direct application of preformed 18-HEPE, etc to hippocampal tissue. However, the second part, in vivo, uses a high-ish dose of EPA or DHA by mouth followed by demonstration of increased plasma levels of 18-HEPE, etc.

 

Preformed Specialized Proresolving Mediators (SPMs, including 18-HEPE, etc.) taken by mouth are destroyed in the digestive process. Pharmacokinetics matter a lot. PLA2, secreted by the pancreas, are the primary enzymes that destroy or otherwise modify fatty substances taken by mouth. However, cytosolic PLA2 (cPLA2) are the enzymes that allow 18-HEPE, etc. to be produced in situ by the cleaving of membrane fatty acids in the brain, for example.

 

This paper: https://www.mdpi.com...8-1989/12/9/826 "A Review of Oxylipins in Alzheimer’s Disease and Related Dementias (ADRD): Potential Therapeutic Targets for the Modulation of Vascular Tone and Inflammation" (2022, full paper) reviews oxylipins and their relationship to vascular tone and inflammation. This specific section labeled "Oxylipins" summarizes the in situ production:

 

"Oxylipins are a broad class of bioactive metabolites formed from the enzymatic and non-enzymatic oxidation of fatty acids. The n-3 class of parent PUFAs are ALA, EPA, and DHA, and the n-6 class of parent PUFAs are LA and AA [25,26]. PUFAs are an integral part of all cell membranes. In the brain, DHA and AA constitute 25% of the total fatty acids in neuronal membranes and contribute to membrane structure and fluidity [26]. Most PUFAs are sequestered as phospholipids in the cell membrane to control the formation of oxylipins [26]. When PUFAs are released from the membrane, they remain in a free fatty acid form very briefly before they are rapidly oxidized and transformed into bioactive oxylipins, which play multifaceted roles in cell signaling, affecting intra- and intercellular metabolism and regulation [25,26,27]. These signaling roles become particularly pronounced upon cell stress and/or injury, which activates cytosolic phospholipase A2 (cPLA2) to cleave specific PUFAs from the membrane producing free fatty acids, with downstream effects on inflammatory markers (e.g., tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)), reactive oxygen species (ROS), and calcium (Ca2+) signaling. Intriguingly, amyloid beta oligomers can also trigger cPLA2 activation [25,27] (Figure 2)."

 

You have to get a high enough dose of EPA/DHA by mouth to meet both of the major functions of omega-3 fats: cell membrane production and SPM production. That dose appears to be 4 grams per day in two divided equal doses per this recommendation: https://www.mdpi.com...6643/14/23/5146 "Update on Omega-3 Polyunsaturated Fatty Acids on Cardiovascular Health" (2022, full paper).

 

Charles Serhan's lab at Harvard first proposed the existence of the need to signal resolution of the necessary inflammatory process and the involvement of oxidation products of omega-3 oils as the signaling compound in ~2000. You can find a lot of really foundational research and summarizing reviews by searching on his name in scholar.google. I think Phillip Calder out of University of Birmingham, UK has also done some really useful research in revealing SPM mechanisms and the inflammatory resolution process.

 

All of that said, yes, before I learned about the pharmacokinetics of omega-3 oils and SPMs, I followed a 6 month protocol using a product from https://prodrome.com/. When I did this the only product they had was a liquid supplied via an impossible applicator with an ostensible purpose of protecting the preformed plasmalogens (a type of SPMs) from storage oxidation. This product had and has the highest concentration of preformed SPMs. Also, $$$. The products mentioned in the OP are minuscule by comparison. The parameter I measured before and after was hs-CRP. The result was no change (between 2 and 3 both before and after). This led me to try to figure out potential reasons why. They include: oxidation of the product in storage (even though it was shipped chilled and stored by me in the refrigerator as recommended) and destruction by the digestive process. Prodrome knew of both of these problems. Their attempt to resolve the storage problem is gelcaps only now.

 

To serve the inflammation resolution signaling need I take 2 grams twice a day with food of Viva Naturals Triple-strength Omega 3 fish oils. After a lot of research, they have the best quality at the lowest price point.

 

Serhan tried to commercialize preformed SPMs via a company Resolvyx Pharmaceuticals formed in 2005. It has since been dissolved. It appears to me that the new approach people are taking to address the very real need for SPMs is to stimulate in situ production of SPMs. So baseline, ingest enough omega-3 oils and then do things to stimulate the enzymes that produce the SPMs natively. This paper discusses some of the pharmaceutical avenues: https://www.annualre...x-051821-042743 "Resolution Pharmacology: Focus on Pro-Resolving Annexin A1 and Lipid Mediators for Therapeutic Innovation in Inflammation" (2023, full paper). One of the OTC means to stimulate in situ production is low dose aspirin. The aspirin-SPMs seems to be particularly resilient to metabolic processes per details in this reference review. 

 

Another thing I learned from my failed preformed SPM self-experiment is that if the trigger of the inflammatory process is not removed, the SPMs can't start the resolution. You can find references via searching on Charles Serhan. Also, efferocytosis is a key part of the resolution process and there are many ways efferocytosis fails. I'm going to stop here.

Edited by CynthesisToday, 19 March 2023 - 04:24 PM.

[elc202]

There is certainly evidence that _if_ 18-HEPE (etc) get to the brain (or other inflammatory site) they can have positive effect in decreasing inflammation and producing measurable improvement in symptoms. See for example: https://www.nature.c...380-021-01160-8 "Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis" (2021, full paper). This paper demonstrates improvement by direct application of preformed 18-HEPE, etc to hippocampal tissue. However, the second part, in vivo, uses a high-ish dose of EPA or DHA by mouth followed by demonstration of increased plasma levels of 18-HEPE, etc.

 

Preformed Specialized Proresolving Mediators (SPMs, including 18-HEPE, etc.) taken by mouth are destroyed in the digestive process. Pharmacokinetics matter a lot. PLA2, secreted by the pancreas, are the primary enzymes that destroy or otherwise modify fatty substances taken by mouth. However, cytosolic PLA2 (cPLA2) are the enzymes that allow 18-HEPE, etc. to be produced in situ by the cleaving of membrane fatty acids in the brain, for example.

 

This paper: https://www.mdpi.com...8-1989/12/9/826 "A Review of Oxylipins in Alzheimer’s Disease and Related Dementias (ADRD): Potential Therapeutic Targets for the Modulation of Vascular Tone and Inflammation" (2022, full paper) reviews oxylipins and their relationship to vascular tone and inflammation. This specific section labeled "Oxylipins" summarizes the in situ production:

 

"Oxylipins are a broad class of bioactive metabolites formed from the enzymatic and non-enzymatic oxidation of fatty acids. The n-3 class of parent PUFAs are ALA, EPA, and DHA, and the n-6 class of parent PUFAs are LA and AA [25,26]. PUFAs are an integral part of all cell membranes. In the brain, DHA and AA constitute 25% of the total fatty acids in neuronal membranes and contribute to membrane structure and fluidity [26]. Most PUFAs are sequestered as phospholipids in the cell membrane to control the formation of oxylipins [26]. When PUFAs are released from the membrane, they remain in a free fatty acid form very briefly before they are rapidly oxidized and transformed into bioactive oxylipins, which play multifaceted roles in cell signaling, affecting intra- and intercellular metabolism and regulation [25,26,27]. These signaling roles become particularly pronounced upon cell stress and/or injury, which activates cytosolic phospholipase A2 (cPLA2) to cleave specific PUFAs from the membrane producing free fatty acids, with downstream effects on inflammatory markers (e.g., tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)), reactive oxygen species (ROS), and calcium (Ca2+) signaling. Intriguingly, amyloid beta oligomers can also trigger cPLA2 activation [25,27] (Figure 2)."

 

You have to get a high enough dose of EPA/DHA by mouth to meet both of the major functions of omega-3 fats: cell membrane production and SPM production. That dose appears to be 4 grams per day in two divided equal doses per this recommendation: https://www.mdpi.com...6643/14/23/5146 "Update on Omega-3 Polyunsaturated Fatty Acids on Cardiovascular Health" (2022, full paper).

 

Charles Serhan's lab at Harvard first proposed the existence of the need to signal resolution of the necessary inflammatory process and the involvement of oxidation products of omega-3 oils as the signaling compound in ~2000. You can find a lot of really foundational research and summarizing reviews by searching on his name in scholar.google. I think Phillip Calder out of University of Birmingham, UK has also done some really useful research in revealing SPM mechanisms and the inflammatory resolution process.

 

All of that said, yes, before I learned about the pharmacokinetics of omega-3 oils and SPMs, I followed a 6 month protocol using a product from https://prodrome.com/. When I did this the only product they had was a liquid supplied via an impossible applicator with an ostensible purpose of protecting the preformed plasmalogens (a type of SPMs) from storage oxidation. This product had and has the highest concentration of preformed SPMs. Also, $$$. The products mentioned in the OP are minuscule by comparison. The parameter I measured before and after was hs-CRP. The result was no change (between 2 and 3 both before and after). This led me to try to figure out potential reasons why. They include: oxidation of the product in storage (even though it was shipped chilled and stored by me in the refrigerator as recommended) and destruction by the digestive process. Prodrome knew of both of these problems. Their attempt to resolve the storage problem is gelcaps only now.

 

To serve the inflammation resolution signaling need I take 2 grams twice a day with food of Viva Naturals Triple-strength Omega 3 fish oils. After a lot of research, they have the best quality at the lowest price point.

 

Serhan tried to commercialize preformed SPMs via a company Resolvyx Pharmaceuticals formed in 2005. It has since been dissolved. It appears to me that the new approach people are taking to address the very real need for SPMs is to stimulate in situ production of SPMs. So baseline, ingest enough omega-3 oils and then do things to stimulate the enzymes that produce the SPMs natively. This paper discusses some of the pharmaceutical avenues: https://www.annualre...x-051821-042743 "Resolution Pharmacology: Focus on Pro-Resolving Annexin A1 and Lipid Mediators for Therapeutic Innovation in Inflammation" (2023, full paper). One of the OTC means to stimulate in situ production is low dose aspirin. The aspirin-SPMs seems to be particularly resilient to metabolic processes per details in this reference review. 

 

Another thing I learned from my failed preformed SPM self-experiment is that if the trigger of the inflammatory process is not removed, the SPMs can't start the resolution. You can find references via searching on Charles Serhan. Also, efferocytosis is a key part of the resolution process and there are many ways efferocytosis fails. I'm going to stop here.

 

Can't thank you enough for your detailed answer.

Many thanks.

[Neurocryo]

I took a bottle from Life Extension as the label directs about 3 years ago.  I noticed a difference the first day but nothing changed over the 30 days or even for weeks afterwards when I wasn’t taking the supplement.  I was 31 when I did this and likely not as inflamed as many people.  I would say give it a shot.

[ironfistx]

I took a bottle from Life Extension as the label directs about 3 years ago.  I noticed a difference the first day but nothing changed over the 30 days or even for weeks afterwards when I wasn’t taking the supplement.  I was 31 when I did this and likely not as inflamed as many people.  I would say give it a shot.

Therefore, either palcebo, or one dose fixed you and you didn't need the rest.