Submit an Article
Online ISSN: 1945-4589
Impact Journals, LLC. is the publisher of Aging: www.impactjournals.com.
Impact Journals is a member of the Wellcome Trust List of Compliant Publishers.
Impact Journals is a member of the Society for Scholarly Publishing.
Learn about our FREE Post-Publication Promotion Services
Research Perspective Volume 8, Issue 8 pp 1578—1582

Fish oil supplements, longevity and aging

João Pedro de Magalhães1, , Michael Müller2, , G. Ed. Rainger3, , Wilma Steegenga4, ,

  • 1 Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
  • 2 Norwich Research Park Food and Health Alliance, Norwich, United Kingdom
  • 3 Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, The Medical School, The University of Birmingham, Birmingham, United Kingdom
  • 4 Division of Human Nutrition, Wageningen University and Research Centre, Wageningen, The Netherlands

Received: June 18, 2016       Accepted: August 16, 2016       Published: August 25, 2016      

https://doi.org/10.18632/aging.101021
How to Cite

Abstract

Fish oil supplementation is of great medical and public interest with epidemiological evidence of health benefits in humans, in particular by conferring protection against heart diseases. Its anti-inflammatory properties have also been reported. Initial results from short-lived mouse strains showed that fish oil can increase lifespan, affecting pathways like inflammation and oxidation thought to be involved in the regulation of aging. Could fish oil and its omega-3 fatty acids act as geroprotectors? Probably not. A new study by Strong et al. challenges the role for fish oil supplementation in aging. Using a large cohort of genetically heterogeneous mice in three sites, part of the Interventions Testing Program of the NIA, Strong et al. show that fish oil supplementation at either low or high dosages has no effect on the lifespan of male or female mice. Although it is still possible that fish oil supplementation has health benefits for specific age-related diseases, it does not appear to slow aging or have longevity benefits.

An increasing number of people are turning to supplements of fish oil and of its omega-3 polyunsaturated fatty acids eicosapenatenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids can only be synthesized in mammals from the dietary precursor and essential fatty acid, α-linolenic acid [1]. However, the synthesis pathway requires a number of elongation and desaturation steps, making direct uptake from the diet a more effective route of assimilation. The EPA and DHA in the human diet are derived indirectly from marine algae (higher plants lack the enzymes for the biosynthesis of these lipids) and their bioavailability is dramatically increased as they pass up the food chain and are concentrated in the flesh of marine fish. Sales of omega-3 supplements have been growing steadily and are valued at over 1 billion dollars in the US alone [2], and omega-3 products in general are worth many billions in sales every year.

The growing public and clinical interest in fish oil and its omega-3 fatty acids is not surprising considering the large number of studies reporting health benefits of fish, fish oil and omega-3 fatty acids consumption. Triggering interest in fish oil were studies conducted in Greenland Eskimos showing that large amounts of fish consumption protected against heart disease, in spite of a large intake of fat and cholesterol [3–6]. Since then several epidemiologic studies have associated reduced risk of cardiovascular disease with fish or fish oil consumption [7–10]. Furthermore, one study in coronary heart patients found that blood levels of omega-3 fatty acids were inversely associated with telomere shortening [11]. Fish oil has been shown to impact on several risk factors associated with coronary heart disease [3]. Briefly, fish oil lowers triglyceride levels [9]. This has been observed in human studies in a dose-response manner, accompanied by increases in LDL cholesterol (and to a lower degree HDL cholesterol) levels [12]. Both EPA and DHA, in fact, have triglyceride-lowering properties [13]. In patients with mild hypertension, but not in healthy subjects, consumption of omega-3 fatty acids has been shown to decrease systolic and diastolic blood pressures [14]. One hypothesis is that, by modulating inflammation within the artery wall, omega-3 fatty acids also alter the structural composition of advanced atherosclerotic plaques in a manner that could reduce the incidence of plaque rupture or ulceration, a process that precedes tissue infarction (e.g. heart attack or stroke) [15].

Although the benefits of fish oil have been more widely studied in the context of heart disease, studies suggest that consumption of fish oil or of its omega-3 fatty acids may have beneficial effects on stroke, depression, diabetes mellitus, cancer and Alzheimer’s disease [3,5,16,17]. Because dietary omega-3 polyunsaturated fatty acids have anti-inflammatory properties, their beneficial effects have been reported for pathologies and conditions associated with inflammation. For example, oral supplements containing omega-3 fatty acids reduced symptoms and clinical scores associated with inflammatory activity in psoriasis [18]. Similarly, fish oil consumption has been shown to reduce the symptoms of disease as well as the use of non-steroidal anti-inflammatory drugs in arthritis patients with severe inflammatory joint disease [19]. One study showed that fish oil supplementation induces anti-inflammatory gene expression profiles in human blood mononuclear cells [20]. In vitro studies have also suggested that omega-3 fatty acids have direct effects on inflammatory responses [21–23].

Numerous studies in mice have supported the beneficial roles of fish oil consumption. Succinctly, in mice, fish oil may have beneficial effects on arthritis [24], cancer [25], cardiac arrhythmias [26] and on bone mass during aging [27]. In murine models of atherosclerosis, the burden of arterial plaque was reduced upon omega-3 fatty acid supplementation [28]. One study reported beneficial effects of dietary omega-3 polyunsaturated fatty acids on toxin-induced neuronal degeneration in an animal model of Parkinson's disease [29].

Fish oil has been shown to increase lifespan by over 40% in autoimmune-prone (NZB x NZW)F(1) female mice [30–33]. Lifespan extension in this NZB/W strain was accompanied by decreased body weight and lowered inflammation levels such as lower NFkB. Interestingly, enhanced antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities were also observed and may partly explain the lower NFkB levels [30,31]. Moreover, a demographic analysis of these fish oil-fed NZB/W revealed that fish oil could shift the Gompertz slope, suggesting that fish oil may delay the rate of aging in NZB/W mice [34]. Another study in mice found evidence of increased antioxidant gene expressions in response to fish oil, though it is possible that this is a defense mechanism since fish oil is easily peroxidized [35]. As such, fish oil affects pathways thought to be involved in the regulation of aging, making it a candidate geroprotector. There is enormous interest in discovering and developing geroprotectors [36], and given that a significant number of people already self administer omega-3 fatty acids for health reasons, evaluating if fish oil is a geroprotector is of great scientific and public interest.

For the above reasons, we proposed fish oil to the Interventions Testing Program (ITP) of the NIA, which investigates the effects of treatments or compounds on the lifespan and aging of mice. Our proposal was approved and two dosages were tested across three sites using a large cohort (n = 287 males and 267 females) of genetically heterogeneous mice. The results reveal no significant longevity benefits of fish oil supplementation of either dose on either sex [37]. A dose-dependent increase in body weight was observed in males at 18 months of age. There was some variation across the three sites with an 18% decline in male longevity observed for the higher dose in one site while a 9% increase in lifespan was observed for males at another site for the lower dosage [37]. Nonetheless, the pooled results do not reveal any significant effects of fish oil on mouse longevity.

Other recent murine studies also raise questions about the health and longevity benefits of fish oil. One small (n =14) study previously found no lifespan effect of fish oil supplementation in female C57BL/6 mice [38]. Another study found fish oil supplementation to shorten mean lifespan in F1 mice by 4.7 to 9.8% [39]. Because NZB/W female mice are slightly obese, autoimmune-prone, short-lived animals, the life extension caused by fish oil in NZB/W mice could be due to a delay of inflammation-triggered pathologies which are more severe in NZB/W mice. Indeed, one more recent study suggests that DHA in particular suppresses IL-18-dependent signaling and glomerulonephritis in NZB/W mice [40]. However, one study found that dietary fish oil in a mouse model of inflammatory colitis induces severe colitis and adenocarcinoma formation [41]. In another short-lived mouse model, long-term dietary fish oil decreased lifespan [42], again suggesting that fish oil’s longevity benefits are limited to very specific strains. Nevertheless, given the importance of inflammation in aging [43], it is surprising that fish oil had no longevity benefits as part of the ITP.

A number of recent clinical trials also failed to substantiate the benefits of fish oil supplements. Of 18 clinical trials and 6 meta-analysis of omega-3 supplements, only 2 reported benefits [2]. Moreover, one recent study found that the indigenous people of Greenland have genetic and physiological adaptations to a diet rich in omega-3 [44]. One possibility is that the benefits of fish oil consumption depend on one's own individual genetic makeup, and some populations will have greater benefits than others. This is not unexpected given that we know that many longevity interventions depend on genome-environment interactions [45]. Although longevity benefits for fish oil supplements seem unlikely, it is still possible that fish oil supplements have a positive impact on specific age-related diseases or conditions. One of the limitations of the ITP study was that no pathological analysis was performed on the animals. Nonetheless, because mice die primarily of cancer, geroprotectors that primarily influence cancer will be more readily detected in mice [46]. One largely unexplored area concerns changes in sensitivity to supplementation with age, in particular if disease is superimposed on the aged. It may be that fish oil supplements are beneficial at some ages and for some conditions but neutral or even detrimental at others. Further studies are necessary to gain clarity on its possibility.

In conclusion, fish oil supplementation does not extend longevity in normal healthy mice. Although specific health benefits of fish oil cannot be excluded, omega-3 fatty acids and fish oil do not appear to act as geroprotectors.

Funding

Work in the lab of JPM is supported by the Wellcome Trust and the Methuselah Foundation. Work in the lab of GER is supported by the British Heart Foundation (PG/11/49/28983; RG/12/7/29693; FS/14/42/30956).

Conflicts of Interest

The authors have no conflict of interest to disclose

References

  • 1. Calder PC. N-3 polyunsaturated fatty acids, inflammation and immunity: pouring oil on troubled waters or another fishy tale? Nutr Res. 2001; 21:309–41. https://doi.org/10.1016/S0271-5317(00)00287-6
  • 2. Grey A and Bolland M. Clinical trial evidence and use of fish oil supplements. JAMA Intern Med. 2014; 174:460–62. https://doi.org/10.1001/jamainternmed.2013.12765 [PubMed]
  • 3. Sidhu KS. Health benefits and potential risks related to consumption of fish or fish oil. Regul Toxicol Pharmacol. 2003; 38:336–44. https://doi.org/10.1016/j.yrtph.2003.07.002 [PubMed]
  • 4. Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr. 1975; 28:958–66. [PubMed]
  • 5. Harris WS. Fish oil supplementation: evidence for health benefits. Cleve Clin J Med. 2004; 71:208–10, 212.
  • 6. Bang HO, Dyerberg J, Hjøorne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand. 1976; 200:69–73. https://doi.org/10.1111/j.0954-6820.1976.tb08198.x [PubMed]
  • 7. Meydani M. Nutrition interventions in aging and age-associated disease. Ann N Y Acad Sci. 2001; 928:226–35. https://doi.org/10.1111/j.1749-6632.2001.tb05652.x [PubMed]
  • 8. Kinsella JE, Lokesh B, Stone RA. Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms. Am J Clin Nutr. 1990; 52:1–28. [PubMed]
  • 9. Kris-Etherton PM, Harris WS, Appel LJ, American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002; 106:2747–57. https://doi.org/10.1161/01.CIR.0000038493.65177.94 [PubMed]
  • 10. He K, Song Y, Daviglus ML, Liu K, Van Horn L, Dyer AR, Greenland P. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation. 2004; 109:2705–11. https://doi.org/10.1161/01.CIR.0000132503.19410.6B [PubMed]
  • 11. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA. 2010; 303:250–57. https://doi.org/10.1001/jama.2009.2008 [PubMed]
  • 12. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997 (Suppl ); 65:1645S–54S. [PubMed]
  • 13. Grimsgaard S, Bonaa KH, Hansen JB, Nordøy A. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. Am J Clin Nutr. 1997; 66:649–59. [PubMed]
  • 14. Bønaa KH, Bjerve KS, Straume B, Gram IT, Thelle D. Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension. A population-based intervention trial from the Tromsø study. N Engl J Med. 1990; 322:795–801. https://doi.org/10.1056/NEJM199003223221202 [PubMed]
  • 15. Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, Gallagher PJ, Calder PC, Grimble RF. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet. 2003; 361:477–85. https://doi.org/10.1016/S0140-6736(03)12468-3 [PubMed]
  • 16. Rose DP and Connolly JM. Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther. 1999; 83:217–44. https://doi.org/10.1016/S0163-7258(99)00026-1 [PubMed]
  • 17. Malasanos TH and Stacpoole PW. Biological effects of omega-3 fatty acids in diabetes mellitus. Diabetes Care. 1991; 14:1160–79. https://doi.org/10.2337/diacare.14.12.1160 [PubMed]
  • 18. Wolters M. Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol. 2005; 153:706–14. https://doi.org/10.1111/j.1365-2133.2005.06781.x [PubMed]
  • 19. Fortin PR, Lew RA, Liang MH, Wright EA, Beckett LA, Chalmers TC, Sperling RI. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol. 1995; 48:1379–90. https://doi.org/10.1016/0895-4356(95)00028-3 [PubMed]
  • 20. Bouwens M, van de Rest O, Dellschaft N, Bromhaar MG, de Groot LC, Geleijnse JM, Müller M, Afman LA. Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells. Am J Clin Nutr. 2009; 90:415–24. https://doi.org/10.3945/ajcn.2009.27680 [PubMed]
  • 21. Collie-Duguid ES and Wahle KW. Inhibitory effect of fish oil N-3 polyunsaturated fatty acids on the expression of endothelial cell adhesion molecules. Biochem Biophys Res Commun. 1996; 220:969–74. https://doi.org/10.1006/bbrc.1996.0516 [PubMed]
  • 22. Denys A, Hichami A, Khan NA. Eicosapentaenoic acid and docosahexaenoic acid modulate MAP kinase enzyme activity in human T-cells. Mol Cell Biochem. 2002; 232:143–48. https://doi.org/10.1023/A:1014806122510 [PubMed]
  • 23. Tull SP, Yates CM, Maskrey BH, O’Donnell VB, Madden J, Grimble RF, Calder PC, Nash GB, Rainger GE. Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment. PLoS Biol. 2009; 7:e1000177. https://doi.org/10.1371/journal.pbio.1000177 [PubMed]
  • 24. Leslie CA, Gonnerman WA, Ullman MD, Hayes KC, Franzblau C, Cathcart ES. Dietary fish oil modulates macrophage fatty acids and decreases arthritis susceptibility in mice. J Exp Med. 1985; 162:1336–49. https://doi.org/10.1084/jem.162.4.1336 [PubMed]
  • 25. Lindner MA. A fish oil diet inhibits colon cancer in mice. Nutr Cancer. 1991; 15:1–11. https://doi.org/10.1080/01635589109514105 [PubMed]
  • 26. Nair SS, Leitch JW, Falconer J, Garg ML. Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action. J Nutr. 1997; 127:383–93. [PubMed]
  • 27. Bhattacharya A, Rahman M, Sun D, Fernandes G. Effect of fish oil on bone mineral density in aging C57BL/6 female mice. J Nutr Biochem. 2007; 18:372–79. https://doi.org/10.1016/j.jnutbio.2006.07.002 [PubMed]
  • 28. Matsumoto M, Sata M, Fukuda D, Tanaka K, Soma M, Hirata Y, Nagai R. Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice. Atherosclerosis. 2008; 197:524–33. https://doi.org/10.1016/j.atherosclerosis.2007.07.023 [PubMed]
  • 29. Bousquet M, Saint-Pierre M, Julien C, Salem N Jr, Cicchetti F, Calon F. Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease. FASEB J. 2008; 22:1213–25. https://doi.org/10.1096/fj.07-9677com [PubMed]
  • 30. Jolly CA, Muthukumar A, Avula CP, Troyer D, Fernandes G. Life span is prolonged in food-restricted autoimmune-prone (NZB x NZW)F(1) mice fed a diet enriched with (n-3) fatty acids. J Nutr. 2001; 131:2753–60. [PubMed]
  • 31. Fernandes G. Progress in nutritional immunology. Immunol Res. 2008; 40:244–61. https://doi.org/10.1007/s12026-007-0021-3 [PubMed]
  • 32. Prickett JD, Robinson DR, Steinberg AD. Dietary enrichment with the polyunsaturated fatty acid eicosapentaenoic acid prevents proteinuria and prolongs survival in NZB x NZW F1 mice. J Clin Invest. 1981; 68:556–59. https://doi.org/10.1172/JCI110288 [PubMed]
  • 33. Prickett JD, Robinson DR, Steinberg AD. Effects of dietary enrichment with eicosapentaenoic acid upon autoimmune nephritis in female NZB X NZW/F1 mice. Arthritis Rheum. 1983; 26:133–39. https://doi.org/10.1002/art.1780260203 [PubMed]
  • 34. de Magalhães JP, Cabral JA, Magalhães D. The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. Genetics. 2005; 169:265–74. https://doi.org/10.1534/genetics.104.032292 [PubMed]
  • 35. Takahashi M, Tsuboyama-Kasaoka N, Nakatani T, Ishii M, Tsutsumi S, Aburatani H, Ezaki O. Fish oil feeding alters liver gene expressions to defend against PPARalpha activation and ROS production. Am J Physiol Gastrointest Liver Physiol. 2002; 282:G338–48. https://doi.org/10.1152/ajpgi.00376.2001 [PubMed]
  • 36. Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut’ko V, Zhavoronkov A, Kennedy BK. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell. 2016; 15:407–15. https://doi.org/10.1111/acel.12463 [PubMed]
  • 37. Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, Javors MA, de Magalhães JP, Martinez PA, et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. Epub ahead of print. https://doi.org/10.1111/acel.12496 [PubMed]
  • 38. Valencak TG and Ruf T. Feeding into old age: long-term effects of dietary fatty acid supplementation on tissue composition and life span in mice. J Comp Physiol B. 2011; 181:289–98. https://doi.org/10.1007/s00360-010-0520-8 [PubMed]
  • 39. Spindler SR, Mote PL, Flegal JM. Dietary supplementation with Lovaza and krill oil shortens the life span of long-lived F1 mice. Age (Dordr). 2014; 36:9659. https://doi.org/10.1007/s11357-014-9659-7 [PubMed]
  • 40. Halade GV, Rahman MM, Bhattacharya A, Barnes JL, Chandrasekar B, Fernandes G. Docosahexaenoic acid-enriched fish oil attenuates kidney disease and prolongs median and maximal life span of autoimmune lupus-prone mice. J Immunol. 2010; 184:5280–86. https://doi.org/10.4049/jimmunol.0903282 [PubMed]
  • 41. Woodworth HL, McCaskey SJ, Duriancik DM, Clinthorne JF, Langohr IM, Gardner EM, Fenton JI. Dietary fish oil alters T lymphocyte cell populations and exacerbates disease in a mouse model of inflammatory colitis. Cancer Res. 2010; 70:7960–69. https://doi.org/10.1158/0008-5472.CAN-10-1396 [PubMed]
  • 42. Tsuduki T, Honma T, Nakagawa K, Ikeda I, Miyazawa T. Long-term intake of fish oil increases oxidative stress and decreases lifespan in senescence-accelerated mice. Nutrition. 2011; 27:334–37. https://doi.org/10.1016/j.nut.2010.05.017 [PubMed]
  • 43. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000; 908:244–54. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x [PubMed]
  • 44. Fumagalli M, Moltke I, Grarup N, Racimo F, Bjerregaard P, Jørgensen ME, Korneliussen TS, Gerbault P, Skotte L, Linneberg A, Christensen C, Brandslund I, Jørgensen T, et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science. 2015; 349:1343–47. https://doi.org/10.1126/science.aab2319 [PubMed]
  • 45. de Magalhães JP, Wuttke D, Wood SH, Plank M, Vora C. Genome-environment interactions that modulate aging: powerful targets for drug discovery. Pharmacol Rev. 2012; 64:88–101. https://doi.org/10.1124/pr.110.004499 [PubMed]
  • 46. de Magalhães JP. Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research. Cell Cycle. 2014; 13:2671–73. https://doi.org/10.4161/15384101.2014.950151 [PubMed]
Download PDF
Corresponding Author

João Pedro de Magalhães
jp@senescence.info

Keywords
fish oil health longevity mice omega-3 fatty acids
Paper Sections