Children of the Corn

One far-off June I drove south from Marquette in the UP down to Kalamazoo, then turned southwest to Champaign. Instead of an 8-hour sprint across the Interstates I navigated 23 hours of blacktop and chert backroads, tacking through green oceans of corn, corn, soy, soy and corn. These oceans cover 200 million acres in all, endless strobing waves of plant life interspersed with an archipelago of silos, a sprinkling of farmhouses and the occasional two-horse four-way outpost.

Each year the US produces almost 500 million tonnes of corn and soy. Where does it all go?

A little goes to plastics, more to ethanol but most of it goes into humans either indirectly, via animal feed, or directly, in food. There are visible food items such as sweet corn, grits, edamame, tortilla chips and soy milk, but the bulk is hidden. It is fed to Americans and the rest of the world in the form of starches, vegetable oils, high fructose corn syrup, soy protein and dozens of other extracts which form the backbone of the ultra-processed foods which dominate our diets today.

I’m not too concerned about soy protein (1). On the other hand, the infiltration of high volumes of high fructose corn syrup and the digestible starches in general into our diet, combined with today’s low levels of physical activity, has wreaked havoc on our public health via metabolic skewing. Metabolic syndrome, type 2 diabetes and related conditions such as hypertension and MASLD are among the most significant pandemics of our times (2, 3).

Then there are soy and corn oils, rich sources of the omega-6 fatty acid linoleic acid (LA) which mammals like us transform into arachidonic acid (AA).

Between 1909 and 1999, estimated per capita consumption of soybean oil increased more than 1000-fold (4). The market for corn oil is smaller but growing rapidly (5), and hit $5.5 billion in 2022. Working in tandem, soy and corn oil have driven up omega 6:3 ratios in the cell membranes of Americans from an estimated 4:1 in Paleolithic times (6, 7) to 16.74 in 1988 (4) and over 25:1 today (8).

In corn-fed Americans, LA now accounts for roughly 10% of all calories ingested (9), much of it hidden in ultra-processed and fast foods (10).

Another factor contributing to increased 6:3 ratios is falling consumption of seafoods, with their payload of the omega-3 fatty acids DHEA and EPA. Where our Paleolithic ancestors swallowed an estimated 660-14,250 mg omega-3 PUFA’s / day (6, 7), we get by on a mere 100-200 mg / day (8,11, 12).

Some say that the inexorable rise in 6:3 ratios in our diet, and therefore tissues, is driving the epidemics of chronic degenerative disease that disfigure public health today. The evidence for this is inconsistent.

Most AA breakdown products are pro-inflammatory, and high intakes of omega-6 fatty acids do reduce the anti-inflammatory effects of fish oil. On the other hand, giving high doses of linoleic and/or arachidonic acid to healthy human volunteers has relatively little effect on inflammatory markers (13, 14); and moderately increased intakes of LA appear to be somewhat cardioprotective (15, 16), via mechanisms which are probably related to shifts in lipoprotein profiles (17).

The fact that increased intakes of LA tend not to lead to increased tissue levels of AA (14) is counter-intuitive. It may be that the abnormally high levels of LA in today’s diet have already saturated the elongase and desaturase enzymes involved in the LA to AA transformation. If so, then these same enzymes would also be unavailable for the ALA-EPA-DHA conversion route, and LA loading could presumably contribute to reduced tissue levels of the 3-LCPUFAs. Conversely, LA depletion should increase them.

There is some limited evidence for this (ie 18, 19), indicating that high LA intakes can indeed lower the omega-3 index and raise the 6:3 ratio, in a pattern widely seen (8) and widely believed to be health-negative (ie 20, 21). So why aren’t high LA intakes more obviously a problem (15, 16)?

The situation with ALA, the parent omega-3 fatty acid, is equally puzzling. Increasing the ALA to LA ratio in the diet has little effect on tissue DHA levels, at least in pre-clinical models (22). Is baseline LA overload enough to explain this (23)? And how important for your health, then, is the LA / ALA dietary ratio?

Let me slip into something more comfortable; the speculative mode.

Cell membranes (which are heterogenous) may be sufficiently heterogenous to contain overlapping but non-identical functional pools of phospholipids containing different fatty acids. In this scenario, the modern diet fills the LA and AA functional pools so that any additional dietary LA or AA is not incorporated into membranes but pushed down other metabolic routes, with potentially variable results; one AA-derived metabolite, lipoxin A4, has substantial inflammation-resolving effects (24, 25).

I’m not convinced by this scenario, but it is at least testable. And now for another sacred cow: if tissue omega-3 levels fall, is this inevitably a bad thing?

Omega-3 metabolites have well-known anti-inflammatory and inflammation resolving properties (ie 26). However, if the inflammation cascade is damped further downstream by other dietary constituents, one could imagine a situation where even as omega-3 levels fall and the 6:3 ratio rises, the overall inflammatory machinery is kept in check.

This is what one finds in India and other tropical regions where dietary omega-3 PUFA’s are scarce, because there is no cold water around those shores. In these populations 6:3 ratios are often 100 or more (8) but their foods are replete with polyphenols, predominantly in spices (27).

The polyphenols inhibit the COX and LOX enzymes at the top of the inflammatory cascade (28), and the matrix metalloprotease enzymes which are released at the bottom of the inflammatory cascade (29-31. This dual anti-inflammatory mechanism protects the extra-cellular matrix from inflammatory / enzymatic damage (ie 29-33). They thus slow the progressive disorganization and loss of tissue that is at the core of inflammageing, driving much of the phenomenology of ageing and the chronic degenerative diseases.

The polyphenols do not work alone. The matrix metalloproteases are also inhibited by Tissue Inhibitors of the Matrix metalloProteases, aka TIMPs, which work in parallel with the polyphenols. Phytonutrients such as lutein which up-regulate TIMP synthesis (ie 34) therefore contribute to overall inflammatory tone.

But this is not the end of the story.

In between the top level of the inflammatory cascade where lipid ratios are important, and the rubber-meets-road end of the cascade where the ECM is degraded, there are intermediate stages which can also be modified by diet. NLRP3 Inflammasome activation, for example, is inhibited by a group of algal- and plant-derived compounds (35) which are not thought of (yet) as anti-inflammatory tools. This group includes lipoic acid, glucosamine, phycocyanobilin, taurine, betaine …

And there is still more.

Plants and plant extracts contain exosome-like nanoparticles, which contain micro-RNA’s, which speak to us when we consume them and modulate inflammatory tone via epigenetic effects. It is yet another demonstration of the unbearable complexity of life.

Fresh rice, for example, provides nanoparticles with a micro-RNA that up-regulates glucose transporter-1 protein in human cells, thereby reducing blood glucose levels and the glycemic index of the rice (36). It also provides a degree of chemo-protection (37). More directly relevant to this post, micro-RNAs from papaya down-regulate genes expressing the pro-inflammatory interleukins 6 and 1B, and up-regulate the genes for the anti-inflammatory cytokine IL-10 (38).

Zizania latifolia (Manchurian wild rice) has another trick up its sleeve. It contains the polyphenol tricin, a flavonoid that inhibits lysosome exocytosis and thus blocks a different link in the inflammatory cascade (39). If tricin can do this, it is likely that other as yet unidentified polyphenols can do the same. These are multi-valent protective phytonutrients!

Clearly, therefore, the relationships between the 6:3 ratio, the omega 3 index and health are not simple, first-order relationships. But we should not have been looking for first-order relationships in the first place. In the world of nutrition there are not many of these, other than in deficiency states; and the concept of specificity that lurks in the background of much of our thinking (the infamous magic bullet) is even less helpful in nutritional biochemistry than it is in pharmacocentric health care.

It is generally the overall dietary mix that is important, rather than any single constituent. The metabolic fuzzy logic bequeathed to us by the evolutionary process that made us omnivores works well enough, providing that we do not stray too far from our dietary origins.

But father, we have strayed …

The modern population consumes excessive amounts of omega-6 vegetable and seed oils, and is depleted in long-chain omega-3 PUFA’s. The ultra-processed diet is also low in polyphenols, the xanthophylls and related compounds that up-regulate TIMPs, and those algal- and plant-derived compounds that down-regulate the inflammasome. Once rice, and papaya and other plants have been ultra-processed, their anti-inflammatory exosomes and their polyphenols are likely stripped away too.

To make matters worse we indulge in a range of pro-inflammatory habits. We smoke, drink, eat too much sugar and starch and fail to take enough exercise.

This is why, blind-sided by the deliberately addictive nature of ultra-processed foods (40, 41), we are sickening and dying in increasingly large numbers (42). Our children, herded and driven into the pen by aggressive marketing campaigns (43), are following us down the slaughterhouse chute (44).

How are you going to keep ‘em down on the farm, after they’ve tasted KFC (45)? They are the true children of the corn.

While the corn and the soy wax, kids are waning in every way except body weight.

The USA and UK are the two nations which consume the most ultra-processed foods, which is why children’s intakes of growth-essential micronutrients in these countries is falling (44, 48). It also explains why, in the USA, children’s height has been declining since the late 80’s / early 90’s (46, 47). In the UK, 5-year-olds have been shrinking since 2013 (44).

At the same time, they are expanding. In the UK, obesity among 10 and 11-year-olds has increased by 30% since 2006, and Type 2 diabetes among under 25s has increased by 22% since 2019 (44). The situation in the USA is worse (47).

Our children’s lives will be shorter and sicker than our own (42, 44, 46-52), and more difficult. The incidence of neurodevelopmental disease continues to rise (48), and the neuroinflammatory stress and generally unfavorable neurochemistry (ie 50-52) created by the modern diet encourages depression and anxiety, and saps impulse control, resilience and intelligence (49-55).

We need to be able to monitor our children’s biochemistry, and rectify it when indicated. But if the concepts of the 6:3 index and the omega-3 index are so incomplete, where does this leave the popular Balance test?

It leaves it firmly on the table, in my opinion, as a useful and clinically valid probe. The Balance test tells us something real about cell membrane structure and function, it shows the biochemical effects of omega-3 PUFA / polyphenol loading, and in many cases it marches so closely in step with clinical improvement that we can estimate an improving test score based on the patient’s declining symptoms.

The Balance test works particularly well in temperate zones, but in global terms the scoring system is more malleable, due to the dietary and regional factors cited above, than they are for standard blood analytes. It may therefore be appropriate to modify the Balance scoring system in the lower latitudes.

6:3 ratios and the 3-index are not the only factor in determining inflammageing, but they are an important contributing factor. In an imprecise and stochastic world, therefore, the Balance Test remains a valuable risk assessment and monitoring tool.

Next week: Galileo, Darwin, Charcot and Margulis. The 4^th Displacement, and how to get home.

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