THANKS FOR ALL THE FISH

Don’t panic. I’m not going to start with a Hitchhiker quote. HHGTTG has not worn well, IMHO, and should be put away with other childish things. If you like science fiction, set the controls for the heart of Vonnegut, Philip K, Ballard, Brunner, Burroughs (William, not Edgar Rice), Gibson, Stephenson, Atwood possibly, even Zelazny. 

Hitchhiker author Douglas Adams died young, of a heart attack, at age 49. If he had eaten more fish he might still be alive, and a better writer¹.

Fish are significantly cardio-protective^2-4, and a growing body of evidence shows that they are good for the brain too. 

Sir Pelham Grenville Wodehouse, an early 20^th century writer and the stylist that Adams would have liked to be⁵, often referred to this⁶. He was correct, even if Bertie Wooster, a life-long member of the Drones and Dunning-Kruger clubs, got the biochemistry wrong. ‘It’s the phosphorus, don’t you know.’ 

Research consistently shows a link between a diet rich in fatty fish and improved cognitive function. There is a haul of publications on the relationship between fish consumption and improved or at least protected cognition, brain volume and structure. The overall data set makes a convincing case for fish, although not for fish oil⁷.

There is mechanistic logic behind this. Neuroinflammatory stress is strongly implicated in hippocampal deterioration⁸ and the pathogenesis of Alzheimer’s⁹. Consuming oily fish reduces chronic inflammation¹⁰ and prevents neuroinflammation¹¹, at least in the most intelligent species on our planet¹².

Epidemiological studies going at least as far back as 1997 found that seafood consumption was associated with a reduced incidence of cognitive decline^13-17 and dementia^18-22. In 2016 a rather good paper was published in JAMA, looking at the relationship between fish consumption and Alzheimer’s pathology. The authors teased apart a series of 286 post-mortem brains and found that that all the key signs of Alzheimer’s Syndrome (AS) including plaques, tangles and clinical scores pre-mortem, correlated inversely with the number of seafood meals consumed per week²³.

Two salient points. In this study, fish oil supplements had no protective effect. And, the protective (anti-inflammatory) effects of fish were only evident in those who carried the APOE ε4 gene, which is known to increase the risk of developing Alzheimer’s. This supports the idea that Alzheimer’s is a syndrome and not a disease in the classic sense, such as cholera or TB; and that there are sub-types of AS in which the inflammatory component is less critical. 

Like Parkinsonism, Alzheimer’s is more accurately seen as a common endpoint collection of neurological abnormalities and symptoms that may have multiple starting points and contributory factors; including over 70 genetic regions, cranial trauma²⁴ and a poor diet^{25, 26}. Not to mention cardiovascular disease, which may itself have multiple causes; and where the vascular component of dementia, cerebrovascular disease, is also reduced by eating fish²⁷.

As with Parkinsonism also, this emphasizes the unsuitability of monotherapy and explains the consistent failure of the pharmaceutical industry to achieve anything more than the moderate and transient management of symptoms²⁸. It also explains the consistent failure of fish oil, an ineffective product because it was designed along pharmaceutical rather than nutritional lines. More on this below.

Back to the fish–brain connection. Another fascinating study looked at the relationship between fish consumption and connectivity in the brain, measured using fractional anisotropy (FA). I may not understand FA (although some of my colleagues would disagree), but I do know that a good FA-BHQ score corelates with cognitive and especially executive function, and trends downwards with aging²⁹. 

A new study out of Kobe, Kyoto and Tokyo found that a good FA-BHQ score also corelated with fish consumption, suggesting that something in fish protects brain micro-anatomy and functional integrity³⁰. Effectively, fish slowed some key aspects of brain ageing. In the images below, white and red are better than green and blue. The first brain makes more connections; it thinks better.

MRI image of the highest FA-BHQ score, from a fish eater

.. and the lowest FA-BHQ score, from a non-fish eater

(Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103640/)

I like these scans because they make brains look like exotic reef fish.

A caveat. This was a small study in nominally healthy subjects, and while fish consumption was linked to connectivity it did not correlate with memory. But it does suggest that increased mental rigidity, so characteristic of the owners of ageing brains, might be avoidable; and that fish consumption would be protective in the 1 in 5 who carry APOE ε4. 

A second US study came out almost at the same time with surprisingly similar results³¹. However, there are inconsistent data with regard to fatty fish, the best sources of omega 3’s with polyphenols, and APOE ε4²¹, so the story is not over yet.

Let us return to the relative uselessness of fish oil⁶. Fish, as with all food³², is more than the sum of its parts. I believe this is why the reductionist (Pasteurian, pharmaceutical) strategy of reducing oily fish to fish oil has been an enduring failure^{7, 33}.

My position is that the removal of the chaperone phlorotannins from commercial fish oil products has contributed to large numbers of premature deaths in those who swallowed the fish oil industry’s hook, line and capsules; many of whom would have lived if they had consumed oily fish instead.

I no longer hold, though, that fish oil is entirely useless. The moving finger of science writes and having writ moves on. While previous meta-analyses left fish oil for dead, the most recent ones (and we should believe them while they are still efficacious) indicate that fish oil can offer some slight benefit.

At least three large studies published within the last 12 months indicate that fish oil supplements may slow atheroma formation and reduce the risk of major cardiovascular events (MACE) by 4-8%, although they fail to reduce the incidence of all-cause death^34-36. There appears to be something positive going on here, although the overall effect remains basically at null.

Within the last 2 years, three other major studies have demonstrated that eating oily fish offers significantly more protection^37-39. They showed a reduction of MACE roughly double that of the fish oil trials and a significant reduction of death from all causes, which is far better than fish oil can do. And they dovetail neatly with the early Zutphen⁴⁰ and DART⁴¹ studies.

Cardiologists and drug company reps will cavil with this reading. They will pick out the first REDUCE-IT trial⁴² in which high dose EPA reduced MACE by 25% in patients with established atherosclerotic cardiovascular disease and/or diabetes and/or elevated triglyceride levels which had not responded to stains. 

This over-priced ($460/month) pharmaceutical product did not reduce the biomarkers associated with atherosclerotic disease⁴³, was only effective in a very specific group of subjects and is generally co-prescribed with a high-dose statin. For these reasons it is entirely unsuitable for preventative use in a public health context.

To recapitulate, oily fish is better than fish oil because it combines the omega 3’s with phlorotannins, produced by the same cold water marine algae that produce the omega 3’s. These two bioactives co-partition through the marine food webs, and through us when we have the good sense to dine on salmon, sardines or sprats.

The omega 3 / phlorotannin combination packs a synergistic anti-inflammatory punch, and work together in two distinct ways. The phlorotannin polyphenols are anti-inflammatory in their own right and some are also amphiphilic^{44, 45}, making them critically involved in the secondary bioavailability and hence functionality of the omega 3’s⁴⁶. 

Phlorotannins have neuroprotective properties also^46-49 (as do a number of fish peptides^50-52), so one can begin to see why eating fish is good for the heart and brain while fish oil is a waste of time and money.

There is a penultimate chapter to this short story. Commercial fish oil is marred not only by what it no longer contains, but also by what this impoverished and unnatural extract breaks down into.

If unprotected by the chaperone polyphenols, the fragile and now vulnerable omega 3 HUFA’s form malondialdehyde, 4-hydroxy-2-hexenal, 4-hydroxy-2-nonenal^53-56 and trans-4-hydroxy-2-hexenal⁵⁴, toxic compounds linked to a number of pathologies⁵⁸. As these likely include neurodegenerative^57-59 and cardiovascular disease^{58, 60}, one’s concerns about commercial fish oil can only continue to mount. 

This is probably not a hugely important mechanism⁶⁰, but it may be enough to contribute to the recorded null effect of commercial fish oil products on all-cause death.

One last reason to jettison fish oil, and order the fish. The marine polyphenols in oily fish, and possibly the amphiphilic polyphenols in particular⁶¹, have distinct anti-cancer effects^63-65. 

Marine phlorotannins can be replaced with olive polyphenols, which have similar properties^66-70. 

If REDUCE-IT is the best that the fish oil industry can do, they have had their chips.

Next Week: Ultra-processed plants and fake wrestling

References

1. Adams was funnier, I think, when working within constrained formats. His notorious Kamikaze sketch is a voice-mail from less sensitive times. https://medium.com/fifteen-minutes-of-mantra-filled-oompah/in-praise-of-the-kamikaze-pilot-sketch-dad0ecb3b256
2. Daviglus ML, Stamler J, Orencia AJ, Dyer AR, Liu K, Greenland P, Walsh MK, Morris D, Shekelle RB. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med. 1997 Apr 10;336(15):1046-53.
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4. Yuan JM, Ross RK, Gao YT, Yu MC. Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China. Am J Epidemiol. 2001 Nov 1;154(9):809-16.
5. Wodehouse is a rapier to Adams’ cudgel. Wodehouse: ‘The fascination of shooting as a sport depends almost wholly on whether you are at the right or wrong end of the gun’. Adams: ‘Make it totally clear that this gun has a right end and a wrong end. Make it totally clear to anyone standing at the wrong end that things are going badly for them. If that means sticking all sort of spikes and prongs and blackened bits all over it then so be it. This is not a gun for hanging over the fireplace or sticking in the umbrella stand, it is a gun for going out and making people miserable with’.
6. https://libquotes.com/p-g-wodehouse/quote/lbc0j6w  Accessed 24.3.23
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Technical University of Denmark Project: PhD, 01/06/2012 → 21/04/2016

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