by Nils Osmar. April 9, 2022
Our bodies, and the aging process, are constrained and regulated by two metabolic processes, AMPK and mTOR. Both processes have been integrated into life on Earth since its beginnings, long before human beings existed. See article.
Discussions around diet, fasting, and exercise, and around compounds like metformin, berberine and rapaymycin come into better focus when we understand their role in activating AMPK and dampening the activation of mTOR. In a nutshell, there appear to be profound health benefits and life-extending benefits to activating AMPK regularly and preventing mTOR from becoming over-activated. We need some mTOR activation, but it’s not good to have it activated all of the time.
Both are Important
- As I mentioned above, AMPK is the longevity pathway. It’s associated with catabolism (recycling the body’s components). When it’s activated in lab animals, they almost always live longer.
- mTOR is the growth pathway. It’s associated with anabolism (growth). When mTOR is activated, we’re building muscles and strengthening our immune systems.
- One way to view them is as a wall light switch which has only two positions. When mTOR is switched “on,” AMPK is usually “off”, and vise versa.
- This is slightly misleading though, because in some situations, mTOR can be activated selectively in different parts of the body, such as the muscles, triggering growth there, without necessarily being activated elsewhere. So we can be “in an AMPK state’ in most of the body while our muscles are “in an mTOR state”.
We can activate AMPK by:
- Fasting (the longer the fast, the greater AMPK activation). AMPK activation when fasting goes hand in hand with the activation of a process called autophagy which cleans accumulated debris out of our cells.
- Exercising (particularly while fasted). See article: “AMPK activation of muscle autophagy...”
- Cold exposure. See article: Upregulation of AMPK during cold exposure…
- Sun bathing. See article.
- Saunas and hot baths See article.
- Eating plant-based meals (low in animal proteins)
- Eating low-protein meals from any source (One caution: There are dangers in letting our protein intake go too low)
- Eating meals low in leucine, an amino acid found primarily in animal foods (but also in nuts and seeds)
- Taking AKG. The form I take is a calcium salt of alphaketoglutarate, Ca-AKG. AKG, like many anti-aging supplements, is – at least under certain conditions – an activator of the AMPK pathway.
- Taking metformin (which both lowers blood glucose and switches on AMPK)
- Taking rapamycin (one of the most potent AMPK activators)
- Taking berberine (which is similar in many respects to metformin)
- Taking milk thistle (which contains silibinin, an AMPK activator)
- Taking allulose (a natural sugar and AMPK activator)
- Taking resveratrol – which also switches on the sirtuin 1 gene and activates neuronal autophagy.
- Drinking coffee. Coffee’s known life-extending benefits are likely related to the fact that it’s a strong activator of AMPK. See article.
- Taking glycine, or eating foods such as gelatin which are high in the amino acid.
- Taking turmeric or cooking with curcumin. See article.
- EGCG from green and white tea
- Ceylon cinnamon (but make sure it’s real Ceylon; Cassia cinnamon is high in coumarin and can be toxic)
- Taking NAD+ boosters like NR, NMN and niacin, and sirtuin activators like fucoidan and cyanidin and resveratrol and quercetin, which are catabolic and tend to activate AMPK.
We can activate mTOR by:
- Eating large amounts of protein
- Eating animal-based foods such as meat and eggs that are high in leucine.
- Eating an omnivorous diet or carnivorous diet.
- Eating high-glycemic carbohydrates. Carbohydrates raise our insulin levels, which in turn activates mTOR.
- Taking anabolic supplements (though some, like creatine, appear to activate both mTOR and AMPK)
Staying in balance
I’m working on building muscle, partly because I like muscularity, partly because I was sliding into sarcopenia (age-related muscle wasting) about a year ago. I describe my journey from muscle wasting to muscle building here.
To build muscles, I need to be deliberately activating mTOR some of the time, But I’m also focused on living longer. So I don’t want to keep it activated full-time. My current strategy is to:
- Get up in the morning (usually around 6 a.m.)
- Take an Ca-AKG supplement (which activates AMPK)
- Have some coffee (a strong activator of AMPK)
- Drink a fasting mimicking smoothie (which keeps AMPK activated)
- I wait until right before starting my workout to take my testosterone boosters (which begin activating mTOR)
- Right after the workout, I eat a high protein, high leucine breakfast and take supplements like creatine, HRB, beta alanine, etc., i.e., anabolic supplements. I’m deliberately activating mTOR, aiming to do so within an hour after the end of my workout. It’s all about timing. Activating it right after a workout keeps the mTOR activation in my muscles, not in the rest of my body where it might have pro-aging effects. I take my hGH and glutathione boosters with this meal.
- Then three or four hours later, I switch to a lower protein, lower leucine approach and start taking AMPK activating supplements such as berberine. I then try to keep AMPK activated the rest of the day.
- My goal is to have AMPK activated most of the time, while selectively activating mTOR around the time of my workouts to help maintain and build muscle (and stave off sarcopenia, a danger associated with the aging process),.
More than one approach
There are lots of approaches. People who want to build massive muscles would focus on keeping their mTOR activated more. But they might be doing so at the cost of a somewhat shortened lifespan. People who don’t care about muscles might focus on keeping their AMPK activated more. But they might be doing so at the cost of muscle wasting, loss of mobility, and weak immune systems.
One reason I’m writing this is because I sometimes see people taking supplements in a kind of ad hoc way. They take their resveratrol or pterostilbene, which are catabolic (AMPK activating), along with their anabolic (mTOR activating) supplements. This could send confusing signals to the body and negate the benefits of taking both.
The truth is that we move naturally between AMPK and mTOR activation as the day moves along. We can intensify this once we understand the underlying mechanisms.
In my own case, I worked out yesterday, then ate a high protein meal, focusing on activating mTOR. Today I’m fasting all day (a 36 hour fast) to activate AMPK.
The studies I’ve read suggest that when we wake up in the mornings, unless we got up several times to snack during the night, AMPK should be activated. When we eat breakfast, assuming that it contains some leucine, mTOR will become activated for a few hours. (mTOR activation can be detected three hours after a high protein meal.) Then it begins to fade, like a fire dying down as it runs out of fuel. When there’s no food is coming in, we start moving back into AMPK. This suggests that it’s possible to move back and forth between mTOR and AMPK activation more than once during a single day. However, some people never experience this because they’re eating and nibbling all day.