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15511Re: [CR] Double bond count and peroxidation

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  • Michael Rae
    Nov 20 8:10 PM

      Dean Pomerleau wrote:
      > Greg Watson wrote:

      > > It would seem that it may be Dean's Omega 6s that are causing the
      > > problem as it is the double bonds that are attacked by free radicals.
      > >
      > > Risk:
      > > Omega 9 ~ 25.8 [double bonds] (17.9 % double bonds here)
      > > Omega 3 ~ 35.7 [double bonds] (24.8 % double bonds here)
      > > Omega 6 ~ 82.6 [double bonds] (57.3 % double bonds here)
      > Very interesting thoughts. It brings of several questions in my mind:
      > 1) Relative peroxidizability as a function of number of double bonds.
      > Your risk estimates seem to assume the peroxidizability is linearly related
      > to the number of double bonds in a fatty acid. This does not seem to be the
      > case.

      Right; this is a key point in the DHA-accelerated aging hypothesis.

      > From Erasmus' book "Fats that Heal, Fats that Kill" (pg. 147):
      > "Triply unsaturated LNA (18:3w3 [ALA]) is most chemically reactive, and
      > spoils most rapidly. It reacts with oxygen about 5 times faster than double
      > unsaturated LA (18:2w6), and LA reacts 2.5 times faster than monounsaturated
      > OA (18:1w9)."

      The overall idea is correct, but his numbers are apparently mistaken, as
      are the pea and lentil peoples' chart. Your analysis, likewise, is right:

      > http://class.fst.ohio-state.edu/FST605/lectures/lect4.html:
      > it appears that conjugated double bonds, like the pair that occurs in LA (1)
      > and ALA (2), result in a very non-linear increase in peroxidizability of the
      > fatty acid. AA appears to have 3 of these conjugated pairs of double bonds,
      > EPA appears to have 4, and DHA has 5, suggesting they would be many times as
      > peroxidizable as even ALA (with 2).

      ... but it isn't as severe as it sounds.

      > Does anyone know of experimental data characterizing the peroxidizability of
      > a wider range of fatty acids (in particular, including AA, EPA and DHA) than
      > the above?

      Pamplona's paper "Mitochondrial membrane peroxidizability index is
      inversely related to maximum life span in mammals" (1) has just such
      information under "calculations and statistics" in "Methods": "The
      peroxidizability index was calculated as PI= [(%monoenoic * 0.025) +
      (%dienoic * 1] + (%trienoic *2) + (%tetraenoic * 4) + (%peantaenoic * 6)
      + (%hexaenoic *8)], citing (2,3). Tho' he asserts that PUFAs' oxidative
      sensitivity "increases as a POWER FUNCTION of the number of double bonds
      PER FATTY ACID MOLECULE", his calculations don't give quite so dramatic
      a picture.

      In arbitrary units, then, the peroxidizability, per molecule, of OA = 1;
      of LA = 4; GLA, DGLA, or ALA, 8; AA, 12; EPA, 16; and DHA, 20.

      > It seems like those numbers would give a much better idea of the
      > relative risk of peroxidation I'm facing from the different fatty acids in
      > my membranes (if we assume GSDL's measures of RBC membrane fatty acid
      > content is representative of other tissues, and more importantly,
      > mitochondrial membranes - a pretty hefty assumption, but again, we don't
      > have anything else to go on).

      It's even LESS likely that your RBC levels reflect mt levels, esp as a CRONie.
      > Just given the highly non-linear peroxidizability data above, it would seem
      > that the contribution of Omega 9, with no conjugated double bonds, would
      > contribute significantly less to my lipid peroxidation than 17.9%, the
      > fraction of my total double bonds it contains.

      Indeed: it would hardly contribute at all, esp as compared to DHA, at
      the other extreme.
      > 2) The second question Greg's thoughtful analysis raises in my mind is one
      > that I think Paul recently raised, namely - what happens to all the ALA I'm
      > consuming that doesn't get incorporated into membranes directly, or
      > converted to EPA? Presumably it is still a target for peroxidation.

      Well, naturally: of course, it's still a target if it IS incorporated
      into membranes or converted into EPA.

      > Could
      > my many-times-typical intake of ALA be the cause of my more than three times
      > the "normal" level of markers for lipid peroxidation (urinary TBARS)?

      Since your TBARS are not such a marker, the question is meaningless.
      Sorry, Dean, but I'll quote it again: "plasma TBARS ... were
      significantly increased in patients
      with HELLP syndrome" yet "lipid hydroperoxides were undetectable (<0.02
      micromol/L)" (4); (5) says that "In some cases, MDA/TBA reactivity is an
      indicator of lipid peroxidation; in other situations, NO QUANTITATIVE OR
      reactivity, and fatty peroxide tone"; and accordingly, "If levels of
      TBARS are increased, other more sophisticated assays should be performed
      for verification."(6) insists that. Using your TBARS as anything other
      than a motivation to get a REAL lipid peroxidation test is IMHO a great
      error. I think it's an error to think you can second guess genuine vs.
      artifactual lipid peroxidation, or interpret the results "cautiously" in
      the absence of confirmatory data: if you use them at all, you've
      accepted their validity, at least for the moment.
      > Some of it will likely get metabolized through the process of oxidation -
      > right? Would the products from this oxidation show up on the urinary TBARS
      > assay?

      If it is truly oxidatively METABOLIZED (burned for fuel), you'll get CO2
      and water, period.

      > As I understand it, fatty acids don't exist in "free" form in very
      > high concentrations - but instead are incorporated into transient vesicles,
      > like particles of HDL and LDL - right? Also, the oxidation of the fatty
      > acids in these cholesterol particles is strongly implicated in
      > cardiovascular disease - right? If so, might a lot of ALA incorporated into
      > non-cellular/mitochondrial membranes be bad news from a CV risk perspective?

      Yes -- but remember that the number of non-SAFA in PL is fixed. If you
      ditch an ALA in a lipoprotein PL, with what will you replace it? MUFA?
      Super! EPA? Trouble.
      > I keep coming back to questioning the best course of action if one places
      > stock (as I do) in Michael Rae's DHA-accelerated aging hypothesis. If we
      > grant for the moment the idea that incorporating DHA into mitochondrial
      > inner membranes (MIMs) is a bad idea from a longevity perspective, what is
      > the best way to avoid getting too much DHA into MIMs, while making sure the
      > body is supplied with sufficient EPA (and to a lesser extent DHA), for its
      > obviously healthful properties?
      > Michael Rae's recommendation has been (and I believe continues to be)
      > avoiding dietary EPA/DHA (fish and fish oil), in favor of dietary ALA (flax
      > seed and particularly flax oil). The idea as I understand it is that a
      > small fraction (about 10%) of the ALA will get converted into the EPA (and
      > then the DHA)

      NB that in humans ""There was an inverse relationship between dietary
      alpha-LA and docosahexaenoic acid concentrations in the phospholipids of
      plasma" (7) & hence in cellular membranes; combine this with the body's
      active anti-DHA mechanisms, & the upregulation of same by CR, and you
      get v. potent anti-DHA mechanism here in MIM. By contrast, the
      conversion of EPA to DPA & DHA is not rate-limited; dietary DHA is
      already preformed. Eating n3 HUFA means that you have to actively GET
      RID of this from MIM, vs. just enhancing whta the body already does if
      you eat ALA.

      > The ALA will also block the
      > conversion of ALA [sic: I presume here you mean "LA," yes?]

      > into GLA, which after a few more steps becomes the harmful
      > AA. Elevated levels of the PUFAs with fewer double bonds (ALA, LA) relative
      > to PUFAs with more double bonds (AA, EPA, DHA) will likely result in less
      > peroxidizable membranes - particularly MIMs. This matches the data showing
      > the MIMs of long-lived species, and CRed animals (right?), have a higher
      > concentration of PUFA's with few double bonds than short-lived species (or
      > AL animals).

      Yes. And, here's some news (to me, tho' it was published in April) from
      Barja's lab:
      increasing the degree of fatty acid unsaturation in heart mt, thru'
      dietary consumption of PUFA, increases "rates of H2O2 production and
      lipid and protein oxidative damage" (8).

      "There is increasing evidence that oxidative stress, specially that
      coming from
      [mt], is implicated in the ageing process [refs]. An important part of
      this evidence comes from comparative animal studies. Among oxidative
      stress-related parameters, which can putatively cause aging, two
      correlate with [max LS] of animal species in the appropriate (inverse)
      sense [and, again, remember, others -- such as conventional antioxidant
      status -- do not!}: the rate of [mt free radicals (ROS)] generation and
      the degree of fatty acid unsaturation [as eg. (1)]."

      "Furthermore, while these two traits can collaborate independently to
      decrease [mt] oxidative damage in long-lived animals, they can also be
      mechanistically interconnected. [mt ROS] production occurs at [MIM],
      which is composed of proteins and lipids. Thus, the low rate of free
      radical generation of the [mt] of long-lived animals can be due to ...
      differences in membrane lipid composition."

      "[S]pecific interactions between particular fatty acids and membrane
      proteins affecting their functions have been described [refs], the
      functionality of the proteins being dependent on the lipidic medium
      (e.g. fatty acid unsaturation)
      in which they are embedded. Thus, the low rate of [mt ROS] generation of
      long-lived animals could also be due in part to the low double bond
      content of their mitochondria."

      "In order to ascertain whether this trait protects mitochondria by
      decreasing lipid and protein oxidation and oxygen radical generation,
      the double bond content of rat heart mitochondrial membranes was
      manipulated by chronic feeding with ... diets rich in highly unsaturated
      (UNSAT) or saturated (SAT) oils" -- to wit, 10% menhaden oil or 9.5%
      fully hydrogenated (no trans-fat) coconut oil, plus 0.5% corn oil to
      avoid EFA deficiency.

      "UNSAT rat heart mitochondria had significantly higher double bond
      content and lipid peroxidation than SAT mitochondria. They also showed
      increased levels of the markers of protein oxidative damage
      malondialdehyde-lysine [an ALE -- no, this is not the same as urinary
      MDA!], protein carbonyls [ROS-damaged proteins esp vulnerable to
      crosslinking because of an aldehyde group], and Ne-(carboxymethyl)lysine
      [AGE] adducts."

      "Basal rates of mitochondrial oxygen radical generation were not
      modified by
      the degree of fatty acid unsaturation, but the rates of H2O2 generation
      stimulated by
      antimycin A were higher in UNSAT than in SAT mitochondria." Antimycin A
      is a Complex III inhibitor; another inhibitor, rotenone, inhibits
      Complex I. (for the uninitiated, ALL mt ROS generation happens when
      CoQ10 "fumbles" an electron between these 2 complexes; this represents
      the great majority of all the ROS to which your body is exposed).

      But when rotenone was added to inhibit Complex I, there was no
      difference between UNSAT & SAT in terms of H2O2 generation. The
      implication: having lots of EPA/DHA around actually increases GENERATION
      of free radicals by cauasing increased fumbling at Complex III.
      "Although the basal rate of free radical generation is not modified, the
      capacity for H2O2 production is higher in UNSAT [mt], and this
      difference occurs at the level of the Complex III generator."

      Why? "While the low double bond content of SAT [mt] primarily protects
      them from lipid peroxidation, it can have also an indirect impact mainly
      on nearby macromolecules since some [ROS], like hydroxyl radical, tend
      to react strongly near their sites of generation. Thus, inner membrane
      proteins would be primary targets", as per the finding of greater mt
      MDA-lysine, protein carbonyls, & CML.

      Furthermore, it jibes with the mitochondrial free radical
      > theory of aging, which says free radical damage to mitochondria (a large
      > part due to lipid peroxidation) is the likely root cause of aging.

      & thru it, mt DNA damage, as mtDNA is literally ATTACHED to MIM &
      peroxidatioin creates chain-reactioins.
      > But is high ALA intake the only way to achieve this result? More
      > specifically, at least I've been working under the assumption that I should
      > be consuming enough ALA to result in "normal" levels of EPA, after the 10%
      > ALA to EPA conversion. But if I'm targeting "normal" levels of EPA in the
      > first place, why not achieve this through very moderate supplementation with
      > EPA-rich (but DHA-poor) OmegaBright capsules? Except for the tendency of
      > the ALA to block conversion of LA to GLA (and eventually to AA), the
      > endpoint seem similar - namely the same "normal" level of EPA, and
      > presumably as a result, the same "adequate" (but not excessive) level of
      > DHA.

      First: don't discount the reduction in AA, which is greater than that
      achievable from direct EPA IF AA intake is low. Second: see above on
      inverse ALA-to-DHA proportionality.

      > This approach has the advantage of requiring me to consume many fewer
      > highly peroxidizable double bonds (by drastically reducing ALA intake),

      But the NUMBER OF MOLECULES of PUFA in MIM & elsewhere is fixed by the
      very nature of PL. It's not like you'd have fewer PUFA MOLECULES
      swirling around in your membranes: you'll have the same number --
      they'll just be EACH more peroxidizable.

      > the new double bonds I am consuming (the EPA in the OmegaBrights) would
      > eventually have been synthesized endogenously from ALA under my current diet
      > in similar quantities anyway (per design), so they don't really add to my
      > peroxidation load.

      This needn't be the case: like most folk, you're thinking that you NEED
      a certain amount of EPA -- which of course you do; studies given
      elsewhere show that as little as 2g of ALA meets this need. This does
      not, however, optimize eicosanoid balance -- but from that POV, as the
      KIM software accurately notes, the task is **TO REDUCE *%* n6 HUFA**; as
      you can do this by driving it out with volume of MUFA or ALA, OR
      reducing its synthesis with ALA, there is no "need" for a given AMOUNT
      of extra ALA.

      > That is why I'm thinking about reducing
      > olive oil to a more moderate level, which will decrease the available LA
      > (since olive oil accounts for about 50% of my daily LA intake), thereby
      > decreasing its downstream metabolite, AA.

      I sympathize with the problem of th eLA in olive oil, & wish I could get
      the stuff removed; but note that the OA drives out AA, and also has
      favorable effects on eicosanoid synthesis, both thru' competing for
      desaturases & thus reducing AA synthesis (9) & also via direct
      inhibition of the formation of AA-derived eicosanoids (9,10 -- & a
      whole post I'm someday going to get around to...) So it's not as if you
      don't get anything, from an eicosanoid POV, out of the OA: you're
      actively achieving the goal of lower tissue %AA, AND reducing the "bad"
      eicosanoids which is the (immediate) goal of lowering the %AA in the
      first place.
      > Michael Rae, I'd very much like to hear your thoughts on this "moderate ALA,
      > moderate olive oil, moderate EPA, low DHA" diet.

      It sux ;).

      > And it entails consuming many
      > fewer double bonds, something I think you'll agree is a good thing - all
      > else being equal (which it is not, I realize).

      Again: at LEAST from an mt POV, it's molecule-per-molecule, as a % of a
      FIXED total UFA, not an increased or decreased number of molecules.
      > Perhaps this is a good intro into the "eicosanoids metabolism" post,

      It would be, yes ... but I'm SUPPOSED to be working on the Albatross update...


      1. Pamplona R, Portero-Otin M, Riba D, Ruiz C, Prat J, Bellmunt MJ,
      Barja G.
      Mitochondrial membrane peroxidizability index is inversely related to maximum
      life span in mammals.
      J Lipid Res. 1998 Oct;39(10):1989-94.
      PMID: 9788245

      2. Holman TR. 1954. Autoxidation of fats and related substances. In
      Holman RT, Lundberg WO, Malkin T (eds), Progress in the Cheistry o fFats
      & Other Lipids, vol 2. Academic Press: New York.

      3. Laganiere S, Yu BP.
      Modulation of membrane phospholipid fatty acid composition by age and food
      Gerontology. 1993;39(1):7-18.
      PMID: 8440492

      4. Diedrich F, Renner A, Rath W, Kuhn W, Wieland E.
      Lipid hydroperoxides and free radical scavenging enzyme activities in
      preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet
      count) syndrome: no evidence for circulating primary products of lipid
      Am J Obstet Gynecol. 2001 Jul;185(1):166-72.
      PMID: 11483923

      5. Janero DR.
      Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of
      lipid peroxidation and peroxidative tissue injury.
      Free Radic Biol Med. 1990;9(6):515-40.

      6. Esterbauer H.
      Estimation of peroxidative damage. A critical review.
      Pathol Biol (Paris). 1996 Jan;44(1):25-8. Review.
      PMID: 8734296

      7. Mantzioris E, James MJ, Gibson RA, Cleland LG.
      Differences exist in the relationships between dietary linoleic and
      alpha-linolenic acids and their respective long-chain metabolites.
      Am J Clin Nutr. 1995 Feb;61(2):320-4.
      PMID: 7840069

      8. Herrero A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G.
      Effect of the degree of fatty acid unsaturation of rat heart
      mitochondria on
      their rates of H2O2 production and lipid and protein oxidative damage.
      Mech Ageing Dev. 2001 Apr 15;122(4):427-43.
      PMID: 11240164

      9. James MJ, Gibson RA, Cleland LG.
      Dietary polyunsaturated fatty acids and inflammatory mediator production.
      Am J Clin Nutr. 2000 Jan;71(1 Suppl):343S-8S. Review.
      PMID: 10617994

      10. Moreno JJ, Carbonell T, Sanchez T, Miret S, Mitjavila MT.
      Olive oil decreases both oxidative stress and the production of
      arachidonic acid
      metabolites by the prostaglandin G/H synthase pathway in rat macrophages.
      J Nutr. 2001 Aug;131(8):2145-9.
      PMID: 11481409

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