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calorie restriction and fatty acid membranes


Paul McGlothin

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All,

 

I have a few comments regarding the fatty acid/membrane discussion, that has occurred in the Society's listserv. I decided to post them here since the forum format lends itself to long-term, coherent discussions. Many observations and comments made in posts in response to Al’s fatty acid post are duplicative of what has been discussed here before. Some is available in the archives. For example, arc.crsociety.org/read.php?2,192840,192913#msg-192913

 

Regrettably though, some posts that go back 10 years or more are lost. So I hope the forum format keeps this subject current and moving forward.

 

The first study of long-term serious calorie restrictors, which Meredith and I organized with with Metametrix Clinical Laboratory, looked at the fatty acid composition of erythrocytes. I'm sorry to say that it remains unpublished. The longer-chain fatty acid composition of most participants’ erythrocyte membranes was very low. This is logical since CR forces cells to burn fats for energy rather than synthesizing new fats for membranes. This is why most of us have such low triglycerides.

 

This effect is mediated in part by adenosine monophosphate protein kinase (AMPK). More about the actions of AMPK can be found here: www.ncbi.nlm.nih.gov/pmc/articles/PMC1483147/. The actions of AMPK are illustrated in the response of the Society to the NIA monkey study: www.crsociety.org/science/nia_monkey_study. Scroll to the center of the page to see it.

 

 

The actions of AMPK are only part of the story. Fortunately, we have CR greats like Al Pater, who force us to continue to think about about fatty acid membranes. Consider these excerpts from the recent paper Al shared. My comments are indented and labeled "PM."

 

On the importance of fatty acid composition of membranes for aging.

Hulbert AJ.

J Theor Biol. 2005 May 21;234(2):277-88. Epub 2005 Jan 24.

PMID:15757684

 

 

Snip

 

 

“Of particular interest for the membrane pacemaker theory of aging is the finding that calorie-restriction is associated with substantial changes in the fatty acid composition of membranes resulting in a decreased susceptibility to lipid peroxidation (Laganiere and Yu, 1987).:

 

PM—this fits with what we observed in the MetaMetrix study

"Since this seminal observation, similar fatty acid changes have been reported for phospholipids from other tissues (Laganiere and Yu, 1991; Tacconi et al., 1991; Laganiere and Fernandes, 1994; Lee et al., 1999; Cefalu et al., 2000), as well as for different classes of liver phospholipids (Cha and Jones, 2000; Jeon et al., 2001). However, some studies have either not found such changes (e.g. Pamplona et al., 2002b and Pamplona et al., 2002c; Ramsey et al., 2004) or have only observed changes following long-term calorie restriction (Lambert et al., 2004). In our laboratory we have found in mice that such membrane changes occur early, are responsive to the degree of calorie restriction, and precede other changes."

 

PM – mice studies like the ones cited are only somewhat relevant to humans. It is a shame that the research groups cited have not found a way to work human subjects.

"Within one month of calorie-restriction there was a significant 25% decrease in the peroxidation index of membranes lipids, but no statistical change in mitochondrial ROS production or tissue antioxidant status (S.C. Faulks, P.L. Else and A.J. Hulbert, unpublished observations)."

 

PM. This is a surprise. I would have thought there would be a statistical increase in ROS due to increased fat burning. However, that might be able to be reduced by low-GI CR, which burns ketones – see the latest paper reported by our friend, Dr. Eric Verdin and colleagues.

“A reduced oxidative stress would be expected to result in greater membrane PUFA content and thus these membrane changes are not the consequence of a reduced oxidative stress (as suggested by some authors) as they are in the opposite direction. They are more likely a causal factor in the reduction in oxidative damage associated with calorie-restriction.”

 

 

“How such changes in membrane composition come about following calorie-restriction is unknown. Merry (2002) suggests there are two possible hormonal candidates; insulin and thyroid hormones. Blood concentrations of insulin and triiodothyronine are significantly lowered by calorie-restriction (see Masoro, 2002). Many studies have shown that low thyroid hormone levels affect membrane fatty acid composition with the most consistent finding being a decrease in the ratio of 20:4/18:2 (see Hulbert, 2000). The lowering of this ratio, with its consequent lowering of the peroxidation-susceptibility of membranes, is a consistent finding of calorie-restriction.

 

PM Excellent observations – likely explanations for the Metametrix Data.

"Similarly, desaturase enzyme activities are decreased when insulin levels fall which will also influence membrane fatty acid composition (Brenner, 1981). In diabetes, phospholipids containing 20:4 decrease while those containing 18:2 increase (McHowat et al., 2000; Head et al., 2000; Han et al., 2000). The potential role of insulin is highlighted by the finding that mitochondrial changes following calorie-restriction in rats are reversed by insulin treatment (Lambert and Merry, 2004)."[br] [br][br]Great paper, Al. Thank you for posting it and to all for your comments.

 

Paul

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All,

 

I have a few comments regarding the fatty acid/membrane discussion, which has occurred in the Society's list serve. I decided to post them here since the forum format lends itself to long-term, coherent discussions. Many observations and comments made in posts in response to Al’s fatty acid post are duplicative of what has been discussed before here. Some is available in the archives. For example, http://arc.crsociety...2913#msg-192913

 

 

Regrettably though, some posts that go back 10 years or more are lost. So I hope the forum format keeps this subject current and moving forward.

 

The first study of long-term serious calorie restrictors, which Meredith and I arranged for with Metametrix laboratories, looked at the fatty acid composition of erythrocytes. It was unfortunately never published. On most participants, the longer-chain fatty acid composition of most participants’ erythrocyte membranes was very low. This is logical since CR forces cells to burn fats for energy rather than synthesizing new fats for membranes. This is why most of us have such low triglycerides.

 

This effect is mediated in part by adenosine monophosphate protein kinase (AMPK). More about the actions of AMPK can be found here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483147/ . The actions of AMPK are illustrated in the response of the Society to the NIA monkey study: http://www.crsociety...ia_monkey_study. Scroll to the center of the page to see it.

 

 

 

The actions of AMPK are only part of the story. Fortunately, we have CR greats like Al Pater, who force us to continue to think about about fatty acid membranes. Consider these excerpts from the recent paper Al shared. My comments are indented and labeled "PM. "

 

On the importance of fatty acid composition of membranes for aging.

Hulbert AJ.

J Theor Biol. 2005 May 21;234(2):277-88. Epub 2005 Jan 24.

PMID:15757684

 

Snip

 

 

“Of particular interest for the membrane pacemaker theory of aging is the finding that calorie-restriction is associated with substantial changes in the fatty acid composition of membranes resulting in a decreased susceptibility to lipid peroxidation (Laganiere and Yu, 1987).:

 

PM—this fits with what we observed in the MetaMetrix study

"Since this seminal observation, similar fatty acid changes have been reported for phospholipids from other tissues (Laganiere and Yu, 1991; Tacconi et al., 1991; Laganiere and Fernandes, 1994; Lee et al., 1999; Cefalu et al., 2000), as well as for different classes of liver phospholipids (Cha and Jones, 2000; Jeon et al., 2001). However, some studies have either not found such changes (e.g. Pamplona et al., 2002b and Pamplona et al., 2002c; Ramsey et al., 2004) or have only observed changes following long-term calorie restriction (Lambert et al., 2004). In our laboratory we have found in mice that such membrane changes occur early, are responsive to the degree of calorie restriction, and precede other changes."

PM – mice studies like the ones cited are only somewhat relevant to humans. It is a shame that the research groups cited have not found a way to work human subjects.

"Within one month of calorie-restriction there was a significant 25% decrease in the peroxidation index of membranes lipids, but no statistical change in mitochondrial ROS production or tissue antioxidant status (S.C. Faulks, P.L. Else and A.J. Hulbert, unpublished observations)."

 

PM. This is a surprise. I would have thought there would be a statistical increase in ROS due to increased fat burning. However, that might be able to be reduced by low-GI CR, which burns ketones – see the latest
reported by our friend, Dr. Eric Verdin and colleagues.

“A reduced oxidative stress would be expected to result in greater membrane PUFA content and thus these membrane changes are not the consequence of a reduced oxidative stress (as suggested by some authors) as they are in the opposite direction. They are more likely a causal factor in the reduction in oxidative damage associated with calorie-restriction.”

 

 

“How such changes in membrane composition come about following calorie-restriction is unknown. Merry (2002) suggests there are two possible hormonal candidates; insulin and thyroid hormones. Blood concentrations of insulin and triiodothyronine are significantly lowered by calorie-restriction (see Masoro, 2002). Many studies have shown that low thyroid hormone levels affect membrane fatty acid composition with the most consistent finding being a decrease in the ratio of 20:4/18:2 (see Hulbert, 2000). The lowering of this ratio, with its consequent lowering of the peroxidation-susceptibility of membranes, is a consistent finding of calorie-restriction.

 

PM Excellent observations – likely explanations for the Metametrix Data.

"Similarly, desaturase enzyme activities are decreased when insulin levels fall which will also influence membrane fatty acid composition (Brenner, 1981). In diabetes, phospholipids containing 20:4 decrease while those containing 18:2 increase (McHowat et al., 2000; Head et al., 2000; Han et al., 2000). The potential role of insulin is highlighted by the finding that mitochondrial changes following calorie-restriction in rats are reversed by insulin treatment (Lambert and Merry, 2004)."

 

 

Great paper, Al. Thank you for posting it and to all for your comments.

 

Paul

 

Hi Paul and Al!

 

I had almost exactly the same reaction to Al's seminal post that you did, Paul. I was especially interested in the note that "Within one month of calorie-restriction there was a significant 25% decrease in the peroxidation index of membranes lipids" -- fascinating!

 

-- Saul

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Paul,

 

Based on the research mentioned above, you had previously recommended supplementing with long chain fatty acids (DHA and EPA), in composite quantities of 1gm per day. The mouse study which started this thread clearly suggests that taking 50% of one's calories from fat in long-chain PFUs is unwise. My normal ratio of omega-6 to omega-3 is around 5 or 6:1. I had actually hoped to have some of the omega-3 incorporated into my cell membranes to suppress the release of inflammatory ecosanoid and prostanoid hormones. At least when I started, I noticed a reduction in allergy symptoms, and have heard similar results from non-CR friends I have recommended fish oil to.

 

Clearly, as our studies of hormesis inform us, the simplistic idea that if some is bad, any is bad, and that if some is good, more is better, is incorrect. Rather, for many substances, what separates the poison from the medicine is the dose. There may be a threshold ratio of long-chain PFUs which separates positive and negative effects.

 

What is your current recommendation on fish oil supplementation?

 

Thanks,

 

Dave

 

 

 

 

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On the topic of including n-3 fatty acids, other than ALA to one's diet, I've read before a study where they tested the mortality from ischemic heart disease in meat eaters, infrequent meat eaters, vegetarians, vegans, and vegans who consumed fish (I guess called pescetarians). The result seemed to indicate that fish eaters had much better odds than the vegans did. I'm not sure how this would fit into all the data, however, I have been eating a salmon a week or so. I think it's likely, as Conrad pointed out early, that the astaxanthin and other antioxidants naturally found in salmon help prevent the omega-3s from any excessive amount of oxidation.

 

http://www.ncbi.nlm.nih.gov/pubmed/10479225

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Paul,

 

Based on the research mentioned above, you had previously recommended supplementing with long chain fatty acids (DHA and EPA), in composite quantities of 1gm per day. The mouse study which started this thread clearly suggests that taking 50% of one's calories from fat in long-chain PFUs is unwise. My normal ratio of omega-6 to omega-3 is around 5 or 6:1. I had actually hoped to have some of the omega-3 incorporated into my cell membranes to suppress the release of inflammatory ecosanoid and prostanoid hormones. At least when I started, I noticed a reduction in allergy symptoms, and have heard similar results from non-CR friends I have recommended fish oil to.

 

Clearly, as our studies of hormesis inform us, the simplistic idea that if some is bad, any is bad, and that if some is good, more is better, is incorrect. Rather, for many substances, what separates the poison from the medicine is the dose. There may be a threshold ratio of long-chain PFUs which separates positive and negative effects.

 

What is your current recommendation on fish oil supplementation?

 

_____________________________________________________________________________________________________________

 

 

Thank you for your comments, Dave. Only a year ago, I continued taking fish oil in a normal dose recommended by supplement manufacturers like Spectrum. That, combined with omega 3s in walnuts, put me in a ratio range like yours of 6:1 Omega 6/3. I noticed no change in immune response. However, I did notice positive changes in lipid subparticles and in cognition. Also with higher doses of EPA, I noticed subtle, yet positive effects on mood as well. Studies provided in CR Way books support this and advocate fish oil consumption. Given that low GI CR produces tremendous burning of fats anyway, I thought my advocacy of fish oil supplementation to be particularly well supported.

 

Nevertheless over the past year, new studies have come to my attention that have caused me to reconsider my recommendation. I am under embargo for one of the studies, since it is still unpublished. Other negative and positive positions on this subject have been posted in the cancer forum on livingthecrway and as soon as time permits, we intend to invite some of the fish oil researchers to be guest on the CR Way expert teleconference series.

 

Studies like this are what has caused me to reconsider: Fish oil linked to increased Risk of Colon Cancer. I had dismissed oxidative stress as a cause for shorter lifespan and in fact, thought ROS signaling to be important for lipid breakdown. Now I am rethinking that and want to hear more from the scientists that produced the negative studies. Presently I am not taking fish oil and suggest that people who take it, read all the literature before continuing.

 

Sorry for the long-winded answer, but I thought you and others reading and responding to this would appreciate an explanation of why my ideas have changed.

 

Paul

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Studies like this are what has caused me to reconsider: Fish oil linked to increased Risk of Colon Cancer. I had dismissed oxidative stress as a cause for shorter lifespan and in fact, thought ROS signaling to be important for lipid breakdown. Now I am rethinking that and want to hear more from the scientists that produced the negative studies. Presently I am not taking fish oil and suggest that people who take it, read all the literature before continuing.

 

 

 

I have had time to read more and I am finding work by Jenifer Fenton ( linked in the above paragraph) showing that Fish oil enhanced with DHA interferes with immune function:

 

 

Dietary fish oil alters T lymphocyte cell populations and exacerbates disease in a mouse model of inflammatory colitis.

 

 

 

 

Cancer Res. 2010 Oct 15;70(20):7960-9. doi: 10.1158/0008-5472.CAN-10-1396. Epub 2010 Aug 26.

 

 

Woodworth HL, McCaskey SJ, Duriancik DM, Clinthorne JF, Langohr IM, Gardner EM, Fenton JI.

 

 

Source

Department of Food Science and Human Nutrition, Department of Pathobiology and Diagnostic Investigation, and College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, USA.

 

 

Abstract

Inflammatory bowel diseases (IBD) increase the risk of developing colorectal cancer. Dietary components that reduce inflammation are associated with lower cancer risk. The long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is present in fish oil and has potent anti-inflammatory properties. The objective of this study is to determine whether dietary fish oil enriched with DHA (DFO) could reduce experimentally induced colitis and colon cancer risk in a mouse model. When SMAD3-/- mice are exposed to Helicobacter hepaticus, mild colitis is observed 4 weeks postinfection.

 

Mice were fed isocaloric diets modified to include corn oil, safflower oil, or DFO (doses ranging from 0.75% to 6.00%) as the fatty acid source for 8 weeks. Mice were gavaged with H. hepaticus; DFO feeding was continued; and mice were sacrificed 4 weeks after infection. The colon and cecum were collected for histopathology. Spleens and mesenteric lymph nodes were collected and analyzed for T-cell populations using flow cytometry. Contrary to expectations, DFO induced severe colitis and adenocarcinoma formation. DFO consumption was associated with decreased CD8(+) cell frequency and diminished CD69 expression on CD4(+) and CD8(+) T-cell populations. Mice consuming DFO also exhibited higher FoxP3(+) CD25(+) CD4(+) T regulatory cell frequency, FoxP3 expression, and altered L-selectin expression during infection. We concluded that DFO-fed mice may be less equipped to mount a successful response to H. hepaticus infection, increasing colon cancer risk. These results support the need to establish a tolerable upper limit for DHA intake particularly in the context of chronic inflammatory conditions such as IBD.

 

PMID:20798218

 

 

This is concerning. If CR has an Achilles heel, it is the ability to react to fast acting bacteria by rapidly producing T cells and probably other cells involved in immune challenges. Now I am asking this question: could normal doses of fish oil impair a CR'ed person's immune response? I don't yet have an answer to that.

 

Paul

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  • 1 year later...

In order to reduce inflammation, I try to have an omega 6:3 ratio of ~2:1 - much like the ratio of human milk.

 

Having said that, I try to keep the amount of PUFA consumed low, <10g / day.

 

The solution to omega 3's supressing the bodies immune response is to eat less omega 3's when ill.

 

Same goes with CR and illness - eat enough calories so your body can fight off illness as needed.

 

You can always return to the CR diet when healthy again.

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In order to reduce inflammation, I try to have an omega 6:3 ratio of ~2:1 - much like the ratio of human milk.

 

Having said that, I try to keep the amount of PUFA consumed low, <10g / day.

 

The solution to omega 3's suppressing the bodies immune response is to eat less omega 3's when ill.

 

Same goes with CR and illness - eat enough calories so your body can fight off illness as needed.

 

You can always return to the CR diet when healthy again.

 

Thank you for your response, SIRT1. Question: what markers do you use to judge your level of inflammation? I ask because most CR folk have very low inflammation levels. Also I think it is very difficult to judge when suppressing the production of natural killer cells is OK, particularly for CR folk. For example, several years ago i was involved in some immune system tests where we were looking at total NK cells and NK activity. By coincidence, I had been bitten by a deer tick and later that day I began to run a high fever. As it turned our my NK cell activity was four times greater than normal. The point I am making is that for many days, I did not know I was coming down with anything. What do you think would have happened if I had suppressed my NK activity with fish oil?.

 

NK cells are involved in many vital activities . I do agree that it may be wise to eat more when illness strikes.

 

Paul

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Thank you for your response, SIRT1. Question: what markers do you use to judge your level of inflammation?

...

 

I've never had my levels of inflammation (eg CRP) tested.

 

... Also I think it is very difficult to judge when suppressing the production of natural killer cells is OK, particularly for CR folk. For example, several years ago i was involved in some immune system tests where we were looking at total NK cells and NK activity. By coincidence, I had been bitten by a deer tick and later that day I began to run a high fever. As it turned our my NK cell activity was four times greater than normal. The point I am making is that for many days, I did not know I was coming down with anything. What do you think would have happened if I had suppressed my NK activity with fish oil?.

 

...

 

To be honest, I really don't know.

 

It's implied that it may have supressed the inflammitory response, but the body may have been fine responding how it did - NK cells may have increased in response to an infection that the tick caused.

 

Have you been tested when healthy, to make a comparison?

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Regarding omega-3 PUFAs and cancer:

 

A systematic review of the literature found no significant link between omega-3 supplementation (largely fish and fish oil) and cancer:

 

Effects of Omega-3 Fatty Acids on Cancer Risk - A Systematic Review

 

 

Regarding the limitations of food study claims:

 

One of the problems with studying fish, fish oil or foods in general is correctly attributing its effects, either to the omega-3 or other compounds present.

 

It could be argued that food studies are mostly unreliable and often overgeneralized (eg fish oil correlations generalized as omega 3), as studied compounds less than 95% pure could be seen as holding significant impurities.

 

Things would be clearer if studies used pure samples of omega-3 oils with vitamin E added to stop autooxidation (see below).

 

A placebo of Vitamin E and a control with neither could also be used, to discern the different effects.

 

 

Fritsche, K. L., & Johnston, P. V. (1988). Rapid autoxidation of fish oil in diets without added antioxidants. The Journal of nutrition, 118(4), 425.

 

 

Feeding of purified diets containing fish oil without added antioxidant leads to rapid autoxidation of the oil and the possibility of artifactual results due to the feeding of autoxidation products. Purified diets containing menhaden oil without any added antioxidant deteriorate quickly. Peroxide value of the diet is elevated 5- to 6-fold within 24 h and 12-fold within 48 h when exposed to air at room temperature. Addition of 0.02% t-butylhydroquinone to the fish oil prevents this deterioration for at least 72 h. Determination of fatty acid composition is not a sensitive indicator of diet integrity. Supplementation of fish oil diets with vitamin E to help protect against in vivo peroxidation is discussed.

 

-------------------

Summary:

- antioxidants (vit E) are encouraged to be added to fish oil / EPA / DHA due to high autooxidation rates.

 

- some negative results may be due to the lack of antioxidants added to the fish oil.

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I have had time to read more and I am finding work by Jenifer Fenton ( linked in the above paragraph) showing that Fish oil enhanced with DHA interferes with immune function:

 

 

Dietary fish oil alters T lymphocyte cell populations and exacerbates disease in a mouse model of inflammatory colitis.

 

...

 

This may be of interest:

 

Regarding fish oil diets and immune response

 

 

Your example suggests that a high DHA fish oil diet may harm immune response.

 

Here is another:

 

Chang, H. R., Dulloo, A. G., Vladoianu, I. R., Piguet, P. F., Arsenijevic, D., Girardier, L., & Pechere, J. C. (1992). Fish oil decreases natural resistance of mice to infection with Salmonella typhimurium. Metabolism, 41(1), 1-2.

 

 

However, there are also cases of fish oil improving survival rates:

 

 

Björnsson, S., Hardardóttir, I., Gunnarsson, E., & Haraldsson, Â. (1997). Dietary fish oil supplementation increases survival in mice following Klebsiella pneumoniae infection. Scandinavian journal of infectious diseases, 29(5), 491-493.

 

Taylor, D. W., Levander, O. A., Krishna, V. R., Evans, C. B., Morris, V. C., & Barta, J. R. (1997). Vitamin E-deficient diets enriched with fish oil suppress lethal Plasmodium yoelii infections in athymic and scid/bg mice. Infection and immunity, 65(1), 197-202.

 

Summary:

Fish oil 3 diets can improve or harm survival rates in mice, depending on the pathogen. Keep in mind negative effects may be due to a lack of antioxidants in the fish oil. Better designed studies are needed.

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