Last update: 7 February 2021
Here is a summary of the linoleic acid chronic disease hypothesis. Please let me know if you have supporting or opposing data that may substantially alter the conclusions (find my email here).
Consumption of linoleic acid (a type of exogenous polyunsaturated fatty acid) is the a major contributor to chronic disease experienced in the westernized world34,35,36,40. Unnaturally high (as compared to pre-agricultural times) consumption of this lipid, well beyond ancestral intakes, causes or contributes to the so-called diseases of civilization – chiefly cardiovascular disease, cancer, diabetes and age-related neurodegeneration – via oxidative stress and metabolic dysregulation.
Ancestral intake of polyunsaturated n-6 fatty acids, in particular of linoleic acid, is low1, even as recently as the early 20th century3. As far as I know, there is only one exception among hunter-gatherers, in the !Kung people2, but this intake may be of relatively recent origin4. Agricultural societies, such as the ancient Egyptians noted for presence of atherosclerosis6, may have had greater than paleolithic intakes of linoleate, but it is far from clear. In the United States of America, intake of of linoleic acid (via vegetable oils) has greatly increased over the last sixty years5, and has likely been rising ever since cottonseed oil was introduced as a food product in the late 19th century7.
Higher linoleic acid concentrations in tissues are associated with lower mortality44,45. However, this cannot be taken to mean that it is causally protective because these are confounded by at least three factors – carbohydrate intake46 (which can’t be assumed to be neutral), diabetes48 (which causally dilutes linoleate47), and genes49.
The omega-3 index is strongly associated with cardiovascular disease30,39, but marine oil supplementation studies show very little effect31. Since n-3 and n-6 compete for enzymes32, this suggests that the excess of n-6 fatty acids is the problem, not the lack of n-3 fatty acids.
There is very little data on association of n-6 fatty acids and cancer33.
Consumption of polyunsaturated oils is associated with age-related macular degeneration34.
Diabetic retinopathy is associated with lower n-3 erythrocyte fatty acids and lower n-3 to n-6 ratio38.
Adipose tissue inflammation in obesity has been linked to polyunsaturated fatty acid peroxidation41.
Experimental data – animals
Linoleate (or its parent vegetable oils) has been shown to:
- contribute to obesity (and by extension – diabetes)8,10,15,17,
- cause heart failure9,17,
- induce mitochondrial dysfunction11,17,
- induce cancer20,
- permit alcoholic damage to liver42,
- dysregulate hypothalamic gene expression43.
Of particular note is the fact that, at least for cancer, there is a threshold value (approximately 4.4% energy) above which there is no further increase in incidence20.
Removal of linoleic acid metabolites is accomplished, apparently, primarily through beta-oxidation12,13, which suggests a low-carbohydrate diet can increase an organism’s tolerance for high linoleic acid intake. This is consistent with data on time-restricted feeding, which also increases beta-oxidation14.
Experimental data – humans
Consistent with the proposed mechanism, reducing linoleate intake also reduces its metabolites16. Reducing linoleate to less than 4% of total energy intake cures non-alcoholic fatty liver disease18, even just replacing cooking oil helps29. Replacing saturated fat with polyunsaturated vegetable fat has been shown to significantly increase mortality in at least one study19 (there are also some that showed non-significant increases19,37) and in total no benefit to the intervention. In general, added n-6 interventions don’t show much benefit50, and what they do is probably a result of simultaneously added n-351.
Consistent with animal studies20, but inconclusive here, is that cancer is not greatly affected by high linoleic intake21, possibly due to the threshold effect.
It seems likely that excess linoleate consumption is a major problem, especially in the context of a high-carbohydrate diet, that has been largely missed due to a preoccupation with cholesterol, and threshold effects of intake. Ceasing to consume excessive (>4%) linoleic acid should eventually (years) resolve these problems, as body fat stores22 and other tissues23 reconstitute with less of it, but some effects may be palpable much sooner, as the bulk of the adipose is long-term storage22, and various tissues have different lifespans.
On a practical level, linoleic acid is very hard to avoid, even if one does not consume these oils or processed foods (where vegetable oils are added). Unprocessed animal foods often contain high amounts of it24,25,26, as monogastric animals are fed high-linoleate feed, which shows up in their products. Beef linoleate, at least, is hardly affected by grain or grass-feeding27. If you’re a farmer, you might want to lower the amount of linoleic acid you feed your animals, since it affects their lipids28 (and probably their health).
Increasing beta-oxidation by restricting carbohydrate and intermittent fasting will probably help to tolerate greater-than-optimal linoleate intake.
A good hypothesis is falsifiable. Therefore, I propose the following methods to potentially refute linoleate’s effects:
- An ad-libitum, inpatient feeding trial matched for protein, carbohydrate and fat, and possibly other relevant factors (like sugar and fiber) but different in levels of n-6 and especially linoleic acid. One arm should have typical western levels (~10 g/d), the other ancestral levels (~1 g/d). Primary outcome – ad libitum calorie intake. Secondary outcome – change in body fat.
- As above, except isocaloric and eucaloric. Primary outcome – change in liver fat from baseline.
- Long-term dietary modification for cardiovascular disease patients, similar to early vegetable oil interventions. Assign people an amount of butter (forbid marganines and mixes) to eat per day, forbid the use of any cooking oils (to reduce the impact of adulteration), track compliance by adipose tissue fatty acid changes over time. Primary outcome – all-cause mortality. Secondary outcome – major adverse cardiovascular events.
- Kuipers, R., Luxwolda, M., Janneke Dijck-Brouwer, D., Eaton, S., Crawford, M., Cordain, L., & Muskiet, F. (2010). Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet. British Journal of Nutrition, 104(11), 1666-1687. doi:10.1017/S0007114510002679
- Katharine Milton, Hunter-gatherer diets—a different perspective, The American Journal of Clinical Nutrition, Volume 71, Issue 3, March 2000, Pages 665–667, https://doi.org/10.1093/ajcn/71.3.665
- Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, Rawlings RR. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr. 2011;93(5):950-962. doi:10.3945/ajcn.110.006643
- Ben-Dor, Miki. (2019). How carnivorous are we? The implication for protein consumption. Journal of Evolution and Health. 3. 10.15310/2334-3591.1096.
- Guyenet SJ, Carlson SE. Increase in adipose tissue linoleic acid of US adults in the last half century. Adv Nutr. 2015;6(6):660-664. Published 2015 Nov 13. doi:10.3945/an.115.009944
- Atherosclerosis and diet in ancient Egypt. A Rosalie David, Amie Kershaw, Anthony Heagerty. Published:February 27, 2010. DOI:https://doi.org/10.1016/S0140-6736(10)60294-2
- Cottonseed Oil. Edible Oil and Fat Products: Edible Oils. Fereidoon Shahidi Won Young Oh Peter J. Wan Phillip J. Wakelyn. First published: 17 February 2020 https://doi.org/10.1002/047167849X.bio022.pub2
- Deol P, Evans JR, Dhahbi J, et al. Soybean Oil Is More Obesogenic and Diabetogenic than Coconut Oil and Fructose in Mouse: Potential Role for the Liver. PLoS One. 2015;10(7):e0132672. Published 2015 Jul 22. doi:10.1371/journal.pone.0132672
- Ghosh S, Kewalramani G, Yuen G, et al. Induction of mitochondrial nitrative damage and cardiac dysfunction by chronic provision of dietary omega-6 polyunsaturated fatty acids. Free Radic Biol Med. 2006;41(9):1413-1424. doi:10.1016/j.freeradbiomed.2006.07.021
- Pan DA, Storlien LH. Dietary lipid profile is a determinant of tissue phospholipid fatty acid composition and rate of weight gain in rats. J Nutr. 1993;123(3):512-519. doi:10.1093/jn/123.3.512
- Schuster S, Johnson CD, Hennebelle M, et al. Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis, and NLRP3 activation in mice. J Lipid Res. 2018;59(9):1597-1609. doi:10.1194/jlr.M083741
- Li Q, Sadhukhan S, Berthiaume JM, et al. 4-Hydroxy-2(E)-nonenal (HNE) catabolism and formation of HNE adducts are modulated by β oxidation of fatty acids in the isolated rat heart. Free Radic Biol Med. 2013;58:35-44. doi:10.1016/j.freeradbiomed.2013.01.005
- Li Q, Tomcik K, Zhang S, Puchowicz MA, Zhang GF. Dietary regulation of catabolic disposal of 4-hydroxynonenal analogs in rat liver. Free Radic Biol Med. 2012;52(6):1043-1053. doi:10.1016/j.freeradbiomed.2011.12.022
- Hatori M, Vollmers C, Zarrinpar A, et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012;15(6):848-860. doi:10.1016/j.cmet.2012.04.019
- Alvheim AR, Malde MK, Osei-Hyiaman D, et al. Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity. Obesity (Silver Spring). 2012;20(10):1984-1994. doi:10.1038/oby.2012.38
- Ramsden CE, Ringel A, Feldstein AE, et al. Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essent Fatty Acids. 2012;87(4-5):135-141. doi:10.1016/j.plefa.2012.08.004
- Ghosh S, Qi D, An D, et al. Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA. Am J Physiol Heart Circ Physiol. 2004;287(6):H2518-H2527. doi:10.1152/ajpheart.00480.2004
- Maciejewska D, Ossowski P, Drozd A, et al. Metabolites of arachidonic acid and linoleic acid in early stages of non-alcoholic fatty liver disease–A pilot study. Prostaglandins Other Lipid Mediat. 2015;121(Pt B):184-189. doi:10.1016/j.prostaglandins.2015.09.003
- Ramsden Christopher E, Zamora Daisy, Majchrzak-Hong Sharon, Faurot Keturah R, Broste Steven K, Frantz Robert P et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) BMJ 2016; 353 :i1246
- Ip C, Carter CA, Ip MM. Requirement of essential fatty acid for mammary tumorigenesis in the rat. Cancer Res. 1985;45(5):1997-2001.
- Zock PL, Katan MB. Linoleic acid intake and cancer risk: a review and meta-analysis. Am J Clin Nutr. 1998;68(1):142-153. doi:10.1093/ajcn/68.1.142
- Hirsch J, Farquhar JW, Ahrens EH Jr, Peterson ML, Stoffel W. Studies of adipose tissue in man. A microtechnic for sampling and analysis. Am J Clin Nutr. 1960;8:499-511. doi:10.1093/ajcn/8.4.499
- Katan MB, Deslypere JP, van Birgelen AP, Penders M, Zegwaard M. Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study. J Lipid Res. 1997;38(10):2012-2022.
- Ripoche A, Guillard AS. Determination of fatty acid composition of pork fat by Fourier transform infrared spectroscopy. Meat Sci. 2001;58(3):299-304. doi:10.1016/s0309-1740(01)00031-6
- Del Puerto M, Cabrera MC, Saadoun A. A Note on Fatty Acids Profile of Meat from Broiler Chickens Supplemented with Inorganic or Organic Selenium. Int J Food Sci. 2017;2017:7613069. doi:10.1155/2017/7613069
- Shapira N, Pinchasov J. Modified egg composition to reduce low-density lipoprotein oxidizability: high monounsaturated fatty acids and antioxidants versus regular high n-6 polyunsaturated fatty acids. J Agric Food Chem. 2008;56(10):3688-3693. doi:10.1021/jf073549r
- Daley, C.A., Abbott, A., Doyle, P.S. et al. A review of fatty acid profiles and antioxidant content in grass-fed and grain-fed beef. Nutr J 9, 10 (2010). https://doi.org/10.1186/1475-2891-9-10
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- Harris WS. Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor. Pharmacol Res. 2007;55(3):217-223. doi:10.1016/j.phrs.2007.01.013
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- Bibus D, Lands B. Balancing proportions of competing omega-3 and omega-6 highly unsaturated fatty acids (HUFA) in tissue lipids. Prostaglandins Leukot Essent Fatty Acids. 2015;99:19-23. doi:10.1016/j.plefa.2015.04.005
- Hanson, S., Thorpe, G., Winstanley, L. et al. Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomised trials. Br J Cancer 122, 1260–1270 (2020). https://doi.org/10.1038/s41416-020-0761-6
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- DiNicolantonio JJ, O’Keefe JH. Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis. Open Heart. 2018;5(2):e000898. Published 2018 Sep 26. doi:10.1136/openhrt-2018-000898
- Simopoulos AP, DiNicolantonio JJ. The importance of a balanced ω-6 to ω-3 ratio in the prevention and management of obesity. Open Heart. 2016;3(2):e000385. Published 2016 Sep 20. doi:10.1136/openhrt-2015-000385
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- Martinelli N, Girelli D, Malerba G, et al. FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J Clin Nutr. 2008;88(4):941-949. doi:10.1093/ajcn/88.4.941
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