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  1. All: Since the turn of the millenium, I've been advancing what I've called the DHA-Accelerated Aging Hypothesis (AKA Michael Rae's Fish oil-Accelerated Aging hypothesis (MiRFAA), an acronym coined by the sorely-missed Michael Sherman to refer to an hypothesis built up from an inference he himself had made from a passing reference in Dr. Aubrey' de Grey's The Mitochondrial Free Radical Theory of Aging). It posits that people on CR should avoid intake of long-chain polyunsaturated fatty acids (LCPUFA), AKA highly-unsaturated fatty acids (HUFA), and especially omega-3 HUFA (DHA and EPA, most often found in fatty fish and fish oil), and especially-especially DHA. This is based on a range of empirical observations which are reviewed at the bottom of this post, and also in the introduction to material recently posted by Al Pater (see also (2) below, although it is from 2007 and comes at the subject from a different theoretical POV than I favor). Instead, one should maximize one's intake of fat from healthy, plant-based monounsaturated fats (and, in particular, high-phenolic, high-oleic extra-virgin olive oil), minimize or eliminate omega-3 HUFA, and get one's essential fatty acids (omega-6 and omega-3) from short-chain sources such as flax oil. However, all the data has been either correlative, or to the extent that it has been experimental, it has been studies of the effects of different interventions on mitochondrial (and, less importantly, tissue) membrane composition. There have been no direct tests of the question: will minimizing the intake of omega-3 HUFA further optimize lifespan in CR experimental animals — and thus, potentially, humans? Now, finally, such a study has been performed and published.(1) Extracts below from extended material posted by Al Pater: Now, before everyone goes out and stocks up on lard (or even coconut oil), let me give three reasons to focus on monounsaturated fats (and, in particular, high-phenolic, high-oleic extra-virgin olive oil) and avoid saturated, despite my advocacy of the "DHA-Accelerated Aging Hypothesis" and the particular use of lard in (1). First, there is a widespread misunderstanding (completely reasonable on its face) that has been cycled around amongst advocates of Paleo, Atkins, and "Ancestral" diets that because there is one more double bod in MUFA than in SaFA, that SaFA must be more resistant to peroxidation. In fact, however, they are not: fatty acids' oxidative sensitivity increases exponentially to (roughly) the number of double bonds minus one, so that MUFA and SaFA alike are virtually unoxidisable (1/40 as much as those with two double bonds, such as linolenic acid). This is illustrated here: (This figure is from (2) below, which is also a good review of the underlying correlational data underlying MiRFAA, although it has a different theoretical explanation for the phenomenon than I or Gustav Barja). But then those with two double bonds are twice as oxidizable as either MUFA or SaFA, those with three doube bonds are twice as oxidisable as those with two, those with four are four times as oxidisable as those with two, and so on. α-linolenic acid (ALA = 18:3 n-3) has THREE double bonds; DHA (22:6 n-3) has SIX. Second, there is the structure of biological membrane phospholipids. The phospholipid structure of the membrane of a cell of a given type is dictated by the functions needed by that cell, so that one cell will have more "phosphatidylcholine" and anther more "phosphatidylethanolamine" and a third more "phosphatidylserine" etc (tho' in fact even these names are rough & ready, and each includes several subspecies). In turn, the internal fatty acid structure of those PL are themselves to an extent determined by their nature. Nearly all PL have to have a saturated fatty acid in their sn-1 position, and nearly all have to have an unsaturated FA in sn-2. In some cases, the particular PL needs a very specific UFA indeed, which is why neither CR nor altering the diet has very much influence on the membrane FA composition of the brain or the retina; but others are much less specific, and any ol' UFA (or a range of UFA) will do. What you are doing by altering your diet, then, is shifting the specific UFA that occupies the sn-2 position of your membrane PL. Even if you WANTED more SaFA in your cell membranes (which, for reasons given above, actually would be of no benefit), eating more SaFA will not get you there. (It may, however, be worth noting that high SaFA intake may have an indirect effect that is beneficial on this narrow question of tissue membrane PL unsaturatioin index if you're also consuming a lot of PUFA, because high SaFA intake increases the activity of delta-9 desaturase, which converts some of the SaFA to MUFA (especially, stearic (18:0) [thanks Brian!] to oleic (18:1)). So a high-SaFA diet can (inefficiently) increase the availability of oleic to compete with PUFA at the sn-2 position, even tho' it has no effect on the am't of SaFA in the tissue membranes. You can see this for animals fed lard in several previous studies linked in my appendix below. But consuming more MUFA directly while limiting PUFA is a more efficient way of doing this). And, finally: remember, while I advocate for this "DHA-accelerated aging hypothesis," it remains an untested one in an experimental sense -- and even I think that its effects will be felt on the margin of things, and only in people on CR. By contrast, the epidemiology and clinical trials are pretty clear that SaFA will kill you dead of a heart attack or occlusive stroke, irrespective of whether you're aging a little slower because of an altered cell membrane composition. Personally, I get all the n3 (5 g ALA) & n6 (12 g LA) I think necessary, and it's all from a small am't (2 tsp) of flax oil and very high-oleic, low-n6 fats (high-oleic, high-polyphenol, premium VF EVOO, plus hazelnuts and a bit of avocado); I certainly wouldn't be using conventional safflower oil, and already choose for other reasons not to consume soybeans. APPENDIX: BACKGROUND ON THE "DHA-ACCELERATED AGING HYPOTHESIS/MiRFAA Further down in this post I give a brief and outdated summary, with an assembly of relevant links to previously-posted data. Here, I present what is the The by now well-established facts which constitute essence of the argument: ------------------------------------------------------------------ 1.Across species, double bond content in the mt inner membrane (MIM) -- and esp DHA content -- is inversely correlated with max LS. http://www.ncbi.nlm.nih.gov/pubmed/?term=9788245+11432462 http://groups.yahoo.com/group/crsociety/message/2980 This effect is particularly impressive in comparing outliers, such as birds, which -- because of their size & high metabolic rate -- would otherwise be predicted to have short LSs (rodents, of similar size & slower metabolic rates, live ~3 yrs; canaries can live > 10 times this long): http://www.ncbi.nlm.nih.gov/pubmed/?term=10337442+10100156+8866736 ------------------------------------------------------------- 2. Within a species, double bond content in MIM increases with aging. https://groups.google.com/forum/?hl=en#!msg/sci.life-extension/0X-nd-3YUIU/za9RsFymjX4J (And de Grey's confirming reply, which nixes my self-imposed caveat): https://groups.google.com/d/msg/sci.life-extension/0X-nd-3YUIU/Fz9Vy3VpT1EJ -------------------------------------------------------------- 3. CR, the most robust and well-studied anti-aging therapy per se (therapies that extend max LS in healthy mammals), retards (2). (Some examples are present in the first post under point (2), above: refs. (1) and (3)). ------------------------------------------------------------------ 4. Feeding all animals yet tested longer-chain PUFA, such as DHA, increases DHA content in MIM. https://groups.google.com/forum/?hl=en#!msg/sci.life-extension/EmmwMfQwgGo/qS-RCQJOx_8J ------------------------------------------------------------------- 5. Specifically, in rodents, feeding fish oil both increases MIM DHA content, AND increases the actual peroxidation of the MIM. https://groups.yahoo.com/neo/groups/crsociety/conversations/messages/2905 Dean's posting of the results is neater: https://groups.yahoo.com/neo/groups/crscience/conversations/topics/7 ---------------------------------------------------- 6. CR opposes the incorporation of dietary EPA/DHA into MIM. https://groups.google.com/forum/?hl=en#!msg/sci.life-extension/d2J6z5WHCsg/rVEzzuduZ7AJ (To understand how these abstracts show this, NB that CL=cardiolipin (diphosphatidylglycerol), a phospholipid only found exclusively (or, some would claim, just OVERWHELMINGLY) in MIM), & MIM contain PL exclusively (no TGs). ----------------------------------------- 7. Although the link is weaker, even solid-organ plasma membrane HUFA levels are inversely related to species max LS in many studies: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10687923&dopt=Abstract ... and CR opposes even organ plasma HUFA, endogenously or from the diet: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10954013&dopt=Abstract http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11485162&dopt=Abstract Important updates on the effects of feeding different fatty acids on tissue membrane fatty acids are here. ------------------------------------------------------------------ 8. The Ames dwarf mouse, a well-studied and very robust life-extended mutant, also has far lower DHA in its solid organ plasma membranes than wild-type mice: http://www.longecity.org/forum/topic/41110-dha-accelerated-aging-hypothesis/?view=findpost&p=602820 [Edit: added 2014-11-03] ------------------------------------------------------------------ 8. DC, Ma, and Id mouse lines (wild-derived mice with significantly greater lifespans than laboratory strains) also exhibit low membrane peroxidation index. Hulbert AJ, Faulks SC, Harper JM, Miller RA, Buffenstein R. Extended longevity of wild-derived mice is associated with peroxidation-resistant membranes. Mech Ageing Dev. 2006 Aug;127(8):653-7. Epub 2006 Apr 18. PubMed PMID: 16620917; PubMed Central PMCID: PMC2929641. [Edit: Added 2014-11-12] ----------------------------------------------------------------------- Inductive conclusion, from the above & a few other tidbits: eating DHA will lead to more DHA in MIM and tissue membranes; more DHA in MIM and tissue plasma membranes correlates with aging within and across species, and is actively opposed by normal organisms -- an effect upregulated in CR. Eating DHA causes effects which parallel the 'normal' aging process and which oppose known effects of CR, the only proven anti-aging intervention in mammals. So don't eat DHA. References 1. The Influence of Dietary Fat Source on Life Span in Calorie Restricted Mice. López-Domínguez JA, Ramsey JJ, Tran D, Imai DM, Koehne A, Laing ST, Griffey SM, Kim K, Taylor SL, Hagopian K, Villalba JM, López-Lluch G, Navas P, McDonald RB. J Gerontol A Biol Sci Med Sci. 2014 Oct 13. pii: glu177. [Epub ahead of print] PMID:25313149 2. Life and death: metabolic rate, membrane composition, and life span of animals. Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA. Physiol Rev. 2007 Oct;87(4):1175-213. Review. PMID: 17928583 [PubMed - indexed for MEDLINE]
  2. Many of us have been conflicted over the long-chain omega-3 fatty acid DHA. On the one hand, it is known to be important for brain health. But on the other hand, Michael has long advocated keeping dietary intake of DHA and EPA low, especially for CR folks, since they are so easily damaged through peroxidation. Plus as I've pointed out, the primary natural food source of DHA/EPA is fatty fish, which pose a problem both for vegans, and for those who want to avoid ingesting heavy metals and pesticides which bioaccumulate in the fat of fish. As a result, people advocate getting one's omega-3s through alpha-linolenic acid (ALA) instead of DHA/EPA, by consuming flax seeds/oil, canola oil or walnuts. The problem with this approach is that the conversion of ALA into DHA/EPA is very limited, so it is not clear if one is getting sufficient DHA through this strategy. With this background, a new study [1] is quite exciting. It found that the combination of ALA and curcumin, one of the active compounds in the spice turmeric, increases the conversion of ALA into DHA, resulting in a 60% increase in the level of DHA in the hippocampal region of the brains of rats fed ALA+curcumin. Furthermore, feeding the combination of curcumin and ALA to rodents decreased their anxiety, suggesting that the DHA was having a beneficial behavioral effect in these rats. Here are the graphs from the full text showing the boosting of hippocampal DHA levels by ALA+curcumin (left) and the increase in time spent in the anxiety-provoking open arm of an elevated radial maze (right), illustrating reduced anxiety when rats were treated with ALA+curcumin: So despite Michael's flippant dismissal of curcumin in this post, in which he wrote: ... and you'll come up with a lot of rank nonsense ;) . Almost nothing that has been said about turmeric or curcumin has been validated in vivo, still less in normal mammals, and nearly nothing in humans — not even epidemiology: when you dig down into the few such studies on 'curries,' they aren't usually even on turmeric-based Indian curries but completely different spice blends from South Asia and the Pacific Islands. Sufficient quantities of curcumin (at levels too high to be obtained from turmeric) seem to lower TG, but (a) there are no long-term outcome studies, (b) the mechanism is unknown, and © CR people (even those on pretty high-carb diets) almost uniformly have very low TG. this study seems to provide strong, in vivo evidence in normal mammals that consuming curcumin may indeed be beneficial for DHA synthesis from ALA, for brain health and for reducing anxiety. The only thing I'm not certain about is dosing - i.e. whether or not the amount of curcumin in the diet of these rats (either 250 or 500 PPM) is reasonable or an unrealistic mega-dose. Perhaps Michael can help decipher the scaling, although I'm not holding my breath, considering how quiet Michael has been on these forums lately . --Dean --------- [1] Biochim Biophys Acta. 2015 May;1852(5):951-61. doi: 10.1016/j.bbadis.2014.12.005. Epub 2014 Dec 27. Curcumin boosts DHA in the brain: Implications for the prevention of anxiety disorders. Wu A(1), Noble EE(1), Tyagi E(1), Ying Z(1), Zhuang Y(1), Gomez-Pinilla F(2). Author information: (1)Department of Integrative Biology and Physiology, University of California at Los Angeles, 621 Charles E. Young Drive Los Angeles, CA 90095, USA. (2)Department of Integrative Biology and Physiology, University of California at Los Angeles, 621 Charles E. Young Drive Los Angeles, CA 90095, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, David Geffen School of medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: fgomezpi@ucla.edu. Full text: http://www.sciencedirect.com.sci-hub.io/science/article/pii/S0925443914003779 Dietary deficiency of docosahexaenoic acid (C22:6 n-3; DHA) is linked to the neuropathology of several cognitive disorders, including anxiety. DHA, which is essential for brain development and protection, is primarily obtained through the diet or synthesized from dietary precursors, however the conversion efficiency is low. Curcumin (diferuloylmethane), which is a principal component of the spice turmeric, complements the action of DHA in the brain, and this study was performed to determine molecular mechanisms involved. We report that curcumin enhances the synthesis of DHA from its precursor, α-linolenic acid (C18:3 n-3; ALA) and elevates levels of enzymes involved in the synthesis of DHA such as FADS2 and elongase 2 in both liver and brain tissues. Furthermore, in vivo treatment with curcumin and ALA reduced anxiety-like behavior in rodents. Taken together, these data suggest that curcumin enhances DHA synthesis, resulting in elevated brain DHA content. These findings have important implications for human health and the prevention of cognitive disease, particularly for populations eating a plant-based diet or who do not consume fish, a primary source of DHA, since DHA is essential for brain function and its deficiency is implicated in many types of neurological disorders. Copyright © 2015 Elsevier B.V. All rights reserved. PMID: 25550171
  3. All, In another apparent micronutrient synergy involving DHA for improved brain health (see Curcumin Elevates DHA in the Brain thread for the other), this new randomized control trial [1] found that supplementing for two years with three B-vitamins (folic acid, B6 and B12) slowed the cognitive decline that often leads from mild cognitive impairment (MCI) to Alzheimer's Disease (AD), but only if the person had "high normal" levels of serum DHA at baseline: When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD. Michael warns against CRers supplementing with DHA, but for brain health it seems that adequate DHA may be important. Curcumin might help increase DHA in the brain by boosting ALA->DHA conversion, but he's also dissed curcumin, so I'm wondering what he thinks of all this... --Dean ---------- [1] J Alzheimers Dis. 2016 Jan 6. [Epub ahead of print] Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. Oulhaj A(1), Jernerén F(2), Refsum H(2,)(3), David Smith A(2), de Jager CA(4). Free full text: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad150777 A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD. PMID: 26757190
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