Dear Mark: GLP-1as and Personality, Diet after Heart Attack, Living to 100, and Peptides

Let’s get right into the questions from the last Q&A. If you want your questions answered in a future post, be sure to upgrade to a paid subscription.

Yeah, I think there’s something to that idea of hunger being an important part of humanity. Hunger is about more than just food. Look at all of the figurative language we have that uses hunger: the starving artist, the hungry entrepreneur. These describe people who are driven to consume or driven to create. Their hunger isn’t just about food. It’s also driving them to greatness, to push boundaries.

In fact, one of the acute effects of ghrelin, which is the hunger hormone whose receptors are targeted by these drugs, is to also increase creativity and cognitive function. Which makes total sense from an ancestral lens. One reason you don’t immediately give up because you’re hungry is because ghrelin is helping push you to new heights. It makes total sense. If you’re going hungry in the wild, you need your wits about you if you’re gonna have a chance to eat and get food. Ghrelin is one of those control mechanisms for that effect.

This is the great mistake that medicine often makes. They highlight one immediate major effect of a hormone or a compound the body makes, and they target it. They inhibit it, they cancel it to stop that one effect without giving as much thought to the fact that the compound may be having other effects that are positive or adaptive. It’s good that people on these drugs aren’t overeating anymore, but they might also be losing their hunger for other things we want people desiring and chasing.

We also see that it seems to affect reward processing in the brain in response to junk food, nicotine, caffeine, alcohol, and perhaps other drugs. Some studies are even in the works using the GLP-1 agonists to treat alcoholism. Very cool stuff, but I do wonder if by inhibiting the amount of reward a person derives from junk food or other “bad things,” you may also inhibit the reward derived from achievement or success in the social sphere. The jury is still out.

I could see it make society more stable but less dynamic.

The fact is that some people aren’t cut out to be high-fat dieters. I’m definitely anything but a cholesterol alarmist, but those are way out of whack and indicate that whatever you’re doing isn’t working.

If you do insist on staying high-fat carnivore, you have to understand that some people simply have an adverse response to saturated fat in large amounts. Saturated fat, while being very resistant to oxidation, does increase aggregation of LDL. It is probably not a big deal if you are eating the perfect diet, but many of us still have years of accumulated linoleic acid in our tissues from past diets. So when you get a decent amount of linoleic acid in the LDL plus a good amount of saturated fat that causes aggregation, you have a problem. You end up with LDL that sticks around for a long time and contains enough unstable linoleic acid to oxidize and become atherogenic. And even if the diet is “perfect,” having lipid numbers that high is pretty unprecedented. There just isn’t a lot of research guidance for it.

Basically, what I would do, and again this is not medical advice, just based on my reading of the literature, is to focus on monounsaturated fats and healthy PUFAs to balance out the SFA. That means eating things like olive oil and avocado oil. It means getting your animal fat from meat and fish (both fatty and lean) rather than adding tons of butter to your food. Nothing wrong with butter, I love it, but I don’t see a need to add tons of it. I would eat some dark chocolate, which is high in a specific type of saturated fat called stearic acid that improves energy metabolism, helps mitochondria function better and is neutral to your blood lipids and actually converts to oleic acid in the body.

You would probably do better with more carbs. They can upregulate thyroid function a bit, which will help with LDL receptor activity and LDL clearance. Again, if you insist on staying ketogenic, many keto dieters have good experiences doing carb refeeds on training days even if they stay otherwise ketogenic. Whenever you do eat carbs, whether it’s as a standard part of your diet or as a refeed, keep fats on the lower side.

Another big lever you can pull, though, is to stop overeating. Overeating even safe and healthy nutrient-dense food is the single best predictor of heart disease. All the studies looking at the effects of various macronutrients or fatty acids on atherosclerosis are overfeeding studies. Ultimately, heart disease is about excess energy. When you’re constantly overeating, you are bathing in low level stress. You don’t have to under-eat, but you shouldn’t be overeating. That may mean fasting, skipping breakfast or dinner, maybe skipping an entire day of eating once a week, but mostly it just means not coming away from every meal stuffed. Instead of trying to eat as much as you can get away with, try to eat less. See how little you can eat and still thrive, perform well in the gym, at work, and in your family life.

I would walk as much as you can and as frequently as you can. Move around a lot at a slow pace. That means getting a walking desk, taking walking breaks every hour you are sitting, and going for a short walk after meals. 

There are also supplements you can take that really do seem to help. Nattokinase is a good one, with studies using 12k IU per day finding plaque regression and comparing favorably to statins. There is also citrus bergamot.

It’s not so much that the cholesterol is a direct problem, but the fact that the numbers are so lopsided is an indication that something isn’t working and it’s itme to switch things up.

Keep your doctor in the loop and get blood work done as you go to track how things are changing (that goes for everyone, by the way).

I’m gonna skip all the supplements and diet advice and even exercise prescriptions. You probably have the basics down, and I’ll say one thing to focus on is having a reason to continue. You gotta have a reason to get up in the morning, and not just get up, but attack the day. You need to be a happy warrior. Not a David Goggins-style grim, intense warrior where every day is a battle you set out to win. No, you have to be the happy warrior. Push hard and give your all, but do it with a smile on your face. Be joyful. You have to love whatever it is that gets you up and gets you going. Don’t run on stress.

You can’t always achieve both (happiness/joy and intense focus and drive) on the same pursuit. I myself take business extremely seriously, and it’s not always pleasant. It’s not “fun.” It can be very stressful, but I always balance it out with play, leisure, and active leisure, to be specific.

So the main things are having a reason to keep getting up and attacking the day, but also having a source of joy. Play. Something fun and something you take very seriously. If they’re the same thing, that’s great.

This is assuming everything else is handled, like hearing, vision, cognition, and diet. You’re avoiding most processed foods. You’re not overweight. You’re lifting weights at least a couple times a week to maintain muscle, bone density, and physical function. You’re getting lots of low-level physical activity, like walking or even just puttering around. You’re raising your heart rate on a regular basis, building up a sweat, getting good sleep.

Peptides are legit, and I think the future of medicine will in large part come down to advances in peptides. These are strings of amino acids that the body already produces in order to create different physiological effects. What peptide manufacturers are doing is enhancing these, isolating them, and providing delivery systems for them. There’s no question that contained within the body are almost all the keys we need for healing. What medicine tries to do is either replicate those mechanisms, enhance them, or figure out how to unlock or block them when needed.

Peptides in my view have the potential to be more adaptogenic versions of these same mechanisms. Rather than brute force something by giving, say, a statin and blocking an entire physiological pathway, the body can identify and harness a specific peptide that it already produces to perform a function in a manner congruent with the rest of one’s physiology.

I’ve tried BPC-157 and some of the other healing ones and I honestly didn’t notice much, but that’s probably because I was trying to heal an old, already established, and pretty extensive hip injury that actually needed full reconstructive surgery. Tesamorelin stimulates growth hormone release. Won’t be as effective as straight HGH, but it has been shown to reduce visceral fat in humans (a good sign that it’s actually stimulating GH release).

There are tons of vendors out there, and my understanding is that they pretty much get their supply from almost all the same places. I would look for a vendor that provides third-party testing results so you have a better idea of purity. Boutique “men’s health” clinics often offer the same products marked up 10x.

That’s it for today. Thanks for reading everyone.