This Fat-Derived Hormone Reverses Heart Aging (New Science)

Exciting emerging research suggests that a fat-derived hormone might hold one key to reversing heart aging. And you can increase levels of this hormone today. Not with drugs or supplements, but with a simple lifestyle intervention.

I promise we'll get to that.

But first, I want to break down new data about how your fat cells make this lipid hormone, how it declines with age, and how this hormonal descent contributes to cardiovascular aging, and then I promise we'll get to what specific lifestyle interventions you can use to increase levels of this hormone to or beyond youthful levels.

Now, the primary paper I want to discuss was recently published in Nature Communications, boasting a title that does the topic as much justice as if one were to label the mystical golden lion Aslan from the Narnia series— maybe you know it— as just a cat. But jokes aside, I know your eyes may glaze over when I say, "Hey, we're talking about 12,13-dihydroxy-9Z-octadecanoic acid and how it attenuates CaMKII function." But I promise we're going to make this interesting and understandable and relevant. And for the record, it's way more fun to say 12,13-DiHoMi, which is kind of the abbreviation of that big scary word I already said. So going forward, Even if it's not the actual pronunciation, we're just going to call this molecule 12,13-DHOMI. We cool? Anyway, perhaps you've heard of brown fat. This is a black shirt, so I kind of missed the point, but brown fat, a type of fat tissue that is specialized to produce heat. This is called thermogenesis. Brown fat protects against the cold and is often discussed in nutrition, metabolism, and biohacker circles because of its impressive ability to burn calories. Burns calories even more than muscle. But that simplistic view of brown fat as just a calorie furnace has led many to overlook its more important role.

Brown fat is a particular type of endocrine organ, a hormone-secreting organ that alters metabolism and physiology in meaningful ways. And one class of hormones that's particularly interesting that's made by brown fat and other fat are the oxylipins.

These are metabolites of polyunsaturated fats like omega-3 and omega-6 fats.

And one specific oxylipin that's gaining attention is this 12,13-DHOME, a derivative of omega-6 fats, specifically linoleic acid. In a nutshell, the researchers found that 12,13-DHOME levels decrease with age in both human and animals alongside a decrease in brown fat activity. This decline is associated with decreased cardiovascular function, as 12,13-DHOME acts in the heart to keep it functioning optimally. We'll get into more specifics in a moment, but fat-sinatingly, transplanting brown fat from young animals to old animals, or directly treating older animals with 12,13-DHOME, it restores youthful cardiovascular function. And this suggests a special lipid compound, this 12,13-DHOME, could act as an anti-aging hormone on the heart. And here's the kicker—I've already teased it but I will again—there are things you can do today without pills or pokes to boost 12,13-DHOME levels. I promise we will get to that, I'm sorry I keep teasing you, but first let's look at some more data, get some more specifics on the table. These bar graphs show 12,13-DHOME levels decreasing with age similarly in aged mice and aged humans compared to their younger counterparts. This helps to establish conservation of physiology across species and supports the human relevance of the animal studies that followed. So what you see here, what you see next is a schematic and the results of brown fat transplantation. Basically, brown fat was taken from young mice, 12 weeks old in this case, and transplanted into the abdominal cavity, the visceral cavity of older mice, 21 months old.

And what did this do?

This brown fat transplant improved cardiovascular function.

I won't walk through all the parameters from the paper, but I've highlighted one that I can explain quite easily called ejection fraction.

Ejection fraction is an important measure of how much blood the heart pumps out with each beat.

If you went to medical school, you'll definitely have heard of it. We use it a lot in medicine.

And ejection fraction tends to decline with age. And as you can see, the brown fat transplant, literally placing brown fat from young animals into the body cavity of an older animal, it was sufficient to restore ejection fraction function to more youthful levels. That's really interesting.

It's really cool, quote unquote. That'll make more sense later.

It's also worth noting that brown fat transplantation increased levels of 12,13-DHOMI.

And when researchers boosted 12,13-DHOMI levels using another method, not a brown fat transplant, but brace yourself for another big term, tissue nanotransfection with epoxide hydroxylase 1 and 2. Yeah, scientists aren't really good at naming things.

But the results were similar. The punchline is: just boosting 12,13-DHOMO levels is sufficient to improve and rejuvenate cardiovascular function.

And by the way, if you want the nuance notes on things like tissue nanotransfection, just see the associated newsletter linked below. And on that, and as a quick shameless plug, you can see all these details at staycuriousmetabolism.com, my newsletter, where you can usually find more details and more papers than what I cover on this channel, as well as exclusive content that doesn't always make it to video, like my review on fasting for Alzheimer's disease, or my deep dive into metabolic psychiatry, or email exchanges and Q&As that I have with members of the research teams whose studies I cover. So I just want to say, if you're like 1213Daihomi and not saturated— get it?— with information from this YouTube channel, then I encourage you to check out staycuriousmetabolism.com. Anyway, shameless plug aside, let's get back to the main story. How? How does 12,13-DHOMI protect against cardiovascular aging?

Well, it's still being investigated, but there are at least two biological mechanisms that were highlighted in this paper.

First, 12,13-DHOMI combats something called ER stress, or endoplasmic reticulum stress. I know, I'm battering you with big words, but I know you can handle it.

This is a cellular condition that arises when the endoplasmic reticulum in the cell can't fold and process proteins properly. This leads to an accumulation of misfolded bad proteins. And if this ER stress is prolonged, it can lead to cellular damage, death, and dysfunction.

Again, I know I'm battering you with terminology, but just think of ER stress as one of the core pillars of aging and metabolic dysfunction, like things you might have heard about, oxidative stress and inflammation. You can put ER stress in that bucket.

And big picture, 12,13-Dihomie helps reduce this ER stress, this metabolic dysfunction. And second, 12,13-Dihomie fights against a process called perivascular fibrosis.

What does this mean? Peri means around, vascular vessels, fibrosis, hardening of the vessels. So basically what it's saying is 12,13-Dihomie helps keep blood vessels more flexible and more functional.

This is again really important for protecting against cardiovascular aging. And 12,13-Dihomi protects against perivascular fibrosis and thereby cardiovascular aging.

Now, I just want to complete the picture since we've gone so far down the jargon rabbit hole and just point out the control switch that it's actually acting on. 12,13-Dihomi is acting on— it's called CaMKII. It's just an enzyme. Basically, 12,13-Dihomi inhibits CaMKII and by doing so helps restore youthful metabolic cardiac function. Inhibits perivascular fibrosis, inhibits ER stress, yada yada yada.

But summarizing, big picture: aging is often seen as an unstoppable decline, but this study offers a counterpoint. 12,13-DHOMI, a lipid hormone secreted by brown fat tissue, it declines with age, and this decline contributes to poorer heart function. And boosting levels of this 12,13-DHOMI hormone either through brown fat transplants or direct interventions to boost 12,13-DHOME, it restores cardiovascular health, at least in aging animals. Now, with that foundation in place, there are practical, non-invasive ways to elevate this hormone and potentially anti-age your heart.

I'm not talking about pills, pokes, or gene therapy.

I'm actually talking about— Now, before we move on, a quick tangent. I want to thank the sponsor of this video, Chapter. I know sponsored messages can feel like a pill, but bear with me, this one's important and could save your life, or your parents' lives. First, here's a transparency statement from me.

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There are practical, non-invasive ways to elevate this hormone and potentially anti-age your heart.

I'm not talking about pills, pokes, or gene therapy.

I'm actually talking about cold exposure. Yeah, a cold shower, a cold plunge. It's a proven way to increase 12,13-DHOMI levels. For example, in one study that I actually already covered on this channel, 64 adults were exposed to 2 hours of cold near their shivering threshold, and this led to a 39% increase in 12,13-DHOMI levels along with a broad spectrum of changes related to oxylipins, predicted to improve cardiovascular health. I actually spoke with the first author of this research, published last year in Cell Reports Medicine, and if you want to hear what the author had to say, you can navigate to 7 minutes and 22 seconds in this video.

And as a quick aside, I do know I said 2 hours near the shivering threshold. I don't know what the minimal exposure is to get a significant boost in 12,13-DHA levels. That's still an area of explanation. I did want to say that.

But that brings us to the next fascinating chapter of this metabolic story. Not all individuals have the same ability to make 12,13-DHOMI and related oxylipins even when exposed to cold or at baseline. And while you might assume that people with more overall fat tissue would make more of this fat-derived hormone, the biological reality is the opposite. There is an inverse association, a negative correlation between body mass index and 12,13-DHOMO levels. So basically, the less fat you have, the more 12,13-DHOMO you make? Kind of odd, but also sensible. And there's also an inverse association between insulin sensitivity and 12,13-DHOMO levels, and between triglycerides, so fat in the blood, and 12,13-DHOMO levels. This relationship is more than just a correlation, at least likely more than just a correlation. Prior researchers demonstrated that in addition to remodeling the heart, 12,13-DHOMO increases fat metabolism by increasing the uptake of circulating fats through specialized fat transporters called FATP1 and CD36, especially in response to cold exposure. So it makes sense that more 12,13-DHOMO would lead to actually lower fat in the blood.

It's all very cool— I told you that quotation mark would make sense later—

but just as to go on another tangent, it's very cool how you can demonstrate the functional consequences on fat tissue of increased 12,13-DHOME levels. So, for example, in one study, researchers injected mice with fat combined with something called a luciferin conjugate. It's a molecule that glows after being taken up by fat cells. So basically, when you expose the animals to 12,13-DHOME, you can literally track the luciferin glow as a proxy for fat uptake and utilization by brown fat tissue. Because to add a layer of complexity, by expressing the enzyme that actually causes the glow only in specific tissues, say brown fat and not white fat, you could pinpoint exactly where and into what tissue fats are being used.

Mind blown yet, or did I lose you?

Anyway, what this all boils down to, again, taking a step back, Cardiac function, it declines with age, in part due to falling levels of this fat-derived hormone, 12,13-DHOME. But restoring 12,13-DHOME levels, it improves cardiac function. It rejuvenates the heart at both the molecular and functional levels. And while technologies like TNT patches may one day be available to you, right now you can't use them, but you can increase 12,13-DHOME levels with routine cold exposure. And putting two and two together, this means routine cold exposure can maybe hormonally slow cardiovascular aging. And finally, there are inverse associations between BMI and 12,13-DHOMI levels, and between other markers of metabolic health, like insulin sensitivity and triglycerides, and 12,13-DHOMI. So other broader lifestyle interventions, diet, sleep, exercise—those that improve metabolic health may also increase your ability to produce 12,13-DHOMI. It all connects. So, in conclusion, aging might be inevitable, but how fast you age, especially at the molecular level, is far more negotiable than we've been led to believe. 12,13-DHOMI, it's not a magic pill. It's a naturally occurring fat-derived hormone that your body already knows how to make, a molecular messenger that declines with age but can be revived through simple science-backed interventions. What these studies and many like them suggest is powerful, that the road to a younger heart doesn't begin in a pharmacy or surgical suite. It begins with activating the right biology. Stay curious, and if you want more, on the complexities of, say, omega-6 fats, I have these two videos you can check out.

And also, you should check out staycuriousmetabolism.com. But really, just thank you for your curiosity and engaging with me on this channel. It's a true pleasure for me. I hope it's a pleasure for you. Have a good day.