Hormesis: The Guiding Concept Behind Longevity Science

Kelly Clarkson has a song that tells us everything we need to know about longevity science, and I’m going to get it stuck in your head… right… now.

 

“What doesn’t kill you, makes you stronger.”

This, in a sentence, is what hormesis means. As Dr. David Sinclair, one of the world’s leading experts on longevity and anti-aging science, writes in his book Lifespan:

“Hormesis is the idea that whatever doesn’t kill you makes you stronger. A level of biological damage or adversity that stimulates repair processes that provide cell survival and health benefits.”

Let’s take training as an example. We know that exercise is good for us.

If you want to live a longer, healthier life, you should exercise consistently.

However, exercise is stressful for the body. We challenge our heart to pump more blood, our lungs to take in more oxygen, our muscles to contract more efficiently.

Yet, because we stress our body, our lungs, heart, and muscles can respond more effectively the next time.

I’m not going to spell this out, because we all on a basic level understand how exercise works. You do something hard. Your body recovers and then next time it can do more.

Conceptually, this is how almost all of the emerging longevity interventions work.

They place a stress on our body which requires our cells to hunker down and either conserve or recycle resources, or improve efficiency for next time.

Regardless of the specific mechanism, it seems there’s a longevity-boosting effect from dosing our body with various kinds of stress. This is hormesis.

Thank you, Kelly Clarkson. Since You Been Gone is my personal favorite KC song mostly because of A Day to Remember’s 10/10 banger cover.

 

But I digress…

There Are 3 Major Biological Pathways That Improve Longevity.

Well, there are probably a lot more than three. But there are three that are getting the majority of airtime in the latest longevity research. In order to activate them, we need to place our body under some kind of stress, into a state of hormesis.

If you’ve poked around in the longevity space, you’ve probably heard these terms. But if you’re like me, you might be confused at first. So we’re going to break down what they mean, what they do, and how they might help us live longer, healthier lives.

mTOR

mTOR stands for “mammalian target of rapamycin.” If you’re familiar with longevity science, you may recognize rapamycin as a commonly discussed drug for living longer. That’s because it targets this mechanism.

In our cells, the mTOR mechanism can either be “on,” or “off.” When it’s on, it encourages cell growth. When it’s off, it encourages our cells to conserve and recycle.

mTOR is regulated by the presence of amino acids in our bloodstream. In particular, by the essential amino acid leucine, which is abundant in animal proteins.

When we have a nice big steak, it signals to our body that times are good, that we don’t need to conserve our resources.

To improve the overall health of our cells and live longer, we want mTOR to be turned off sometimes. When mTOR is off,  our cells will boost their defenses and recycle proteins. As Sinclair writes, “When our ancestors were unsuccessful in bringing down a wooly mammoth and had to survive on meager rations of protein, it was the shutting down of mTOR that permitted them to survive.” 

So how do you turn off mTOR?

Any interventions that leave our body with less protein, in particular leucine. This includes…

• Fasting. This avoids protein altogether, obviously. (If you’re unfamiliar, we have a whole series on intermittent fasting.)
• Lower protein intake.
• Lower animal protein intake. Plant proteins have fewer BCAAs, which includes leucine. So you can have abundant protein but less mTOR activation. This may be one reason why plant-based diets may show overall improved health outcomes.
• Not taking BCAAs. Whether they help performance is pretty unclear, anyway.
• Rapamycin. This is a prescription-only drug used at high doses as an immune-supressent for those with organ transplants. It has some risks and downsides, but it targets this pathway directly. This is a you-and-your-doctor conversation.

Notice that all of these are stressful for the body. Of course, our body would prefer to be well-fed all of the time. But to deactivate mTOR requires periods of discomfort for our cells. It requires hormesis.

The Paradox of mTOR

If you’ve been in bodybuilding circles, you’ve probably heard about the importance of keeping mTOR on as much as possible. That’s because it encourages muscle growth.

That’s why, again, hormesis comes back to a balance. The reality is, unless you’re a bodybuilder, you’ll want to have mTOR off some of the time. You can still perform exceptionally well (and set yourself up to perform just as well as you age), with periods of fasting or with lower animal protein intake.

The constant activation of mTOR is one theory why bodybuilders, despite exercising a lot and eating lots of healthy food, seem to not live very long. (Excessive PED use is another theory.)

AMPK

AMPK stands for adenosine monophosphate-activated protein kinase, and it’s a major regulator of our blood glucose. Basically, the more AMPK is activated, the lower our blood sugar. Many drugs for diabetics, like metformin (which again, you may be familiar with), act on this bodily mechanism to manage blood.

Constant high blood sugar is, well, very bad. It’s part of the ecosystem of insulin resistance that leads to type II diabetes. In fact, diabetes drugs like metformin target the AMPK pathway directly.

For longevity, we want AMPK to be activated. It means we’ll have our blood sugar in check. How do we do this?

• Fasting.
• Caloric restriction. Reducing overall calories.
• Less sugar. Just in case you needed another reason why sugar is bad for you.
• Exercise. Particularly aerobic exercise.
• Metformin. This is a prescription drug with risks. Talk to your doctor.
• Berberine. I talk a bit more about Berberine in this article. It turns on AMPK. It’s safer than metformin but still has some downsides, so read that article for more.

SIRtuins

The SIR in sirtuins stands for “silent information regulators.” They’re proteins in the cell that regulate our epigenome. They’re the silent but efficient workers that don’t get always get the respect of the office that they deserve.

I like to think of these proteins like a bunch of assistants making sure everybody’s calendars are in-check, that the office is clean, and that everything is running smoothly.

You just need these kinds of people in your life sometimes. And these kinds of proteins in your cells, as well.

They help make sure our DNA stays packaged nice and neatly, which is key for anti-aging effects. As we age, our DNA kind of unravels, so our genes don’t express themselves the way they did at our peak. By activating Sirtuins, we keep more workers on duty to keep our cells in tip-top shape.

Basically: better sirtuins, better genes, and a longer, healthier life.

How do we boost sirtuin activity?

• Caloric restriction.
• Heat and cold exposure.
• Exercise. Exercise boosts NAD levels, which boosts sirtuin activity.
• Resveratrol. This will probably get its own article, but the mechanism of resveratrol targets sirtuin genes.
• NAD booster supplements. With supplements, you can boost NAD directly, which typically declines as we age. This includes NR, NMN, and NAD. I’ve written an article on NMN supplements.

Again, we’re spotting some patterns of interventions. Fasting does all three.

What do these three mechanisms have in common? They activate under some kind of hormesis.

Of course, too much adversity isn’t a good thing, either. For fasting, that’s called malnutrition or starvation. For cold exposure, that’s called hypothermia. And for training that’s called overtraining. You can absolutely overdo it.

So it’s about striking a balance and finding routines that support longevity and stress your body, without stressing it too much.

Training is the perfect metaphor. Obviously, exercise is a healthy kind of stress (and one that’s definitely linked to longevity). But overtraining is NOT healthy.

Does Hormesis Mean You’re Harming Performance?

There’s this idea that’s gaining popularity that if you want to live longer, you have to sacrifice your muscle and performance. You definitely can’t have the best of both at all times. Elite athletes need to be fueling their body, and intermittent fasting, caloric restriction, or other stress-inducing interventions won’t be the best for them during peak competition.

It comes back to prioritizing your goals. You may sacrifice some performance in the short-term, but in 10, 20, or 50 years you may perform like somebody much younger because you will biologically have the cells of somebody much younger.

I’m really interested in top athletes who seem to stave off decline as they age. There’s a balance of top-performance and longevity that I find super interesting about hockey players like Jaromir Jagr and Teemu Selanne.

Even athletes though, while they probably shouldn’t do 16-hour fasts during a hard season, some IF in the offseason might work really well for them.

Second, I generally want to dispel this notion that it’s a tit for tat trade-off. Many interventions improve longevity, health, and performance.

Weight training is one such example. Stronger people are more resistant to falls as they get older, which is a common cause of death-inducing injury. Improving your mobility and athleticism is another.

Eating healthier foods like plants packed with nutrients is a win for the short-term and the long-term. We can say the same for sleep.

Longevity Interventions You Can Actually Apply

While I’m interested in the latest science, I’m most interested in how this can apply to you. Over the next three articles, I’m going to dive into all of the potential longevity interventions and give practical tips to apply them, without derailing your performance or life.

Part 1 will cover nutrition, including what to eat, when to eat, and how much to eat.

Part 2 will cover training, which also includes interventions like cold therapy, sauna, and even red light therapy. I’ll also talk about recovery interventions here.

Part 3 will include everybody’s favorite part: supplements and drugs. It’s annoying because this is probably the least important, and you should really focus on the first two parts. But we’ll talk about it. From NAD boosters, to resveratrol, to prescription-only drugs, to up-and-coming supplements, I’ll cover it all.

Pubmed is bookmarked on my laptop, so you know it’s getting serious.

I want to give a huge shout out to the amazing researchers who’ve been putting so much content out there about longevity, in particular Dr. David Sinclair at Harvard.

I do not see myself as a replacement to the work of researchers. Far from it.

Rather, I view us on different places in a cohesive, strong, chain-link fence to bring science and research into the realm of practicality. Whereas they digest the research and tell you how all of this works, I’ll cover how it works briefly, but focus more on how to apply it.

Understand: inevitably, some details will get lost in the translation. By definition, a translation can’t be the same thing.

For example, I love the Kelly Clarkson quote becuase it’s simple, but it does miss some of the nuances of hormesis. So to go even deeper on these topics, I highly recommend listening to David Sinclair’s podcast.

Have a specific question about longevity or anti-aging? Reach out and let me know. Reader questions help me decide what topics and questions are worth convering. 

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