What’s Eating You? – Lindsay Gray

In the beginning, medicine was messy. Before we had the technology to see into cells, all we had was observation, inference, and good old fashioned knives. And in the very beginning, we didn’t even have the luxury of being able to cut people open to see how everything fit together: in many parts of the world, for religious and cultural reasons, human dissection was strictly off the table. So early students of human form and function had to make do with animals and hope that our own guts were arranged in the same way. If you wanted to be a surgeon in the early Roman empire, you also had serious social stigma working against you, since surgery was considered to be dirty, undignified manual labor by the wealthy upper class. Thankfully for anyone who’s ever studied science or been to a hospital, this didn’t deter Galen, a young philosopher who started out as a gladiatorial medic and ended up authoring stacks of meticulous treatises on human diet and disease that formed the bedrock of much of modern medicine.

In part due to the social strictures of the times, early doctors like Galen were primarily dietitians. Among the models of disease Galen advanced was the idea that optimal health could be achieved through the balance of the “humours” — blood, phlegm, and black and yellow bile — and that excesses or deficits in any of these could be brought about by poor diet or overexertion, leading to specific kinds of symptoms. In a land before syringes and anesthesia, the primary means of removing things from patients were sharp and frightening and often involved fire. So rather than grisly and injurious elimination of disease-causing agents from the body (with a very high potential for the introduction of even more), a focus on food became paramount in treatment, and also became the subject of careful accounts of different diets and their effects.

We seem to find ourselves in a similar situation today. Meal planning and fitness apps are ubiquitous, and meal kit delivery services cater to every possible dietary regimen currently vying for attention as the most effective way to lose weight, boost your mental acuity, and help you live longer. A cursory Google will bombard you with rejoinders to try paleo, keto, plant-based, “clean” lifestyles, assuring you that you’ll reap immediate benefits. I personally embrace the lifestyle choices (if only in theory and not strictly in practice)of Jeanne Calment, whose recorded age at the time of her death was 122. She spent the majority of her century on earth chain-smoking, drinking port wine, eating chocolate, and possibly also lying about her age. Whether or not this last part is true is still contentious but either way, in my mind, it stands as a ringing endorsement for just doing whatever the hell you feel like doing and seeing what happens.

Because a lot of these diets that don’t consist primarily of alcohol and addictive stimulants are restrictive and require skillful nutritional planning, many people find them hard to stick to for prolonged periods of time and turn to more enticing alternatives that dictate when you eat, but not necessarily what you eat. There are many variations on the theme of intermittent fasting, but the basic idea is that you restrict your food intake to a brief window during the day, usually between 8 and 10 hours, and during this time you can eat whatever kinds of food you want (provided you don’t lean too heavily into the port wine and chocolate). The rest of the time, your body switches metabolic gears and initiates pathways that reportedly defend against cancer, protect you from neurodegenerative disease, prolong life, and ultimately guide you down the yellow-brick road to the elusive, magical land of “Optimal Health”.

That yellow-brick road is paved with poorly-controlled studies, weak correlations, and conflicting results that are further muddied by attempts to translate physiological findings across species with fundamentally different physiology. But the basic biology is (mostly) straightforward and many of these claims do have solid support in mice and humans. At the center of the story is your brain: a greedy, glucose-hungry monster that constantly demands attention from the rest of your tireless body. And the easiest place to find glucose is in carbohydrate-rich foods that, for evolutionary reasons, we find highly palatable and tend to binge on around the holidays.

Glucose is the basic building block of all the cellular energy we produce under normal conditions, but when we can’t find glucose, our bodies have to find another way to make it or face the wrath of an angry brain. So we scavenge alternate energy sources stored in our fat and free amino acids that would otherwise be used to make new proteins. This is actually a generalized cellular response to any kind of extreme stress: in lean times, we switch from building things to breaking things down.

Some interesting things start to happen at the intersection of cell biology and behavior. One of these things is that when the stress response pathway is activated and your intracellular protein factories are temporarily shut down for repairs, lots of different kinds of proteins and chemical messengers are produced to aid in this process — a kind of molecular demolition derby and a whole team of highly specialized janitors. The last thing you want at a time like this is more, new junk coming in that you’ll eventually have to find a way to get rid of.

One of the proteins engaged in the cellular stress response pathway is GDF15, a growth factor whose biological functions are so numerous it’s easier to ask what it doesn’t do. But one surprising thing it does seem to do is curb your appetite. Two recent studies found that in both mice and humans at least part of the reason the anti-diabetic drug Metformin is so effective is that it causes people (or mice) to eat less, especially if they’re obese or on a high fat diet. The way it does this is by stimulating the production of GDF15 by chemically triggering the stress response. Other studies in mice have also pointed to GDF15 as a possible gut-to-brain signal of nutritional imbalance. In taste preference tests, when given a choice, mice will learn to actively avoid an otherwise neutral flavor if it’s paired with a dose of GDF15. Elevated levels of the protein have also been found in pregnant women who suffer from severe morning sickness, strongly suggesting that beyond simply keeping you from going back for seconds, GDF15 might just steer you out of the lunch line in the first place.

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