AMPK and mTOR: What They Are and Why They Matter for Longevity

by Nils Osmar. Updated September 16, 2023

AMPK and mTOR are cellular signaling pathways which can be switched on (or off) by the presence or absence of nutrients. They’re deeply integrated into the most basic metabolic pathways of living organisms (including human beings) on Earth.

Benefits and drawbacks of activating AMPK

AMPK (Adenosine Monophosphate-Activated Protein Kinase) is often referred to as the “longevity pathway”. This is not just hyperbole. Lab animals who are kept in a state of AMPK activation, either by being fasted or being fed diets low in leucine or calories, often have unusually long lifespans, sometimes living up to 50 percent longer than their litter-mates.

AMPK becomes activated in response to low energy levels in our cells, a situation that can occur we’re fasting, exercising, and/or eating a diet that’s low in calories, protein and/or other essential nutrients. The longer we fast and the more vigorous our exercise, the more deeply our AMPK is activated, and the deeper our autophagy and apoptosis. See article: AMPK Activation of Muscle Autophagy

The pharmaceutical drug rapamycin is one of the most powerful activators of AMPK. Compounds in supplements such as berberine, benfotiamine, fucoidan (found in seaweed), cyanidin (found in elderberries) and glucosamine have also been found to activate it.

The things that activate AMPK — fasting, exercise and diets that are low in protein and other nutrients — also activate autophagy (a beneficial process that involves the breakdown and recycling of damaged cellular components). and switch on the sirtuin genes, which Dr. David Sinclair believes are “survival genes” supporting improved healthspan and lifespan.

On the down side, when AMPK and autophagy are overactivated, we can experience health problems, including:

1. Muscle wasting or atrophy (Cachexia). If we’re older, overactivating AMPK can trigger age-related muscle wasting, i.e., sarcopenia.
2. Immune function impairment: When AMPK is activated full time, the result is a compromised immune response and increased susceptibility to infection.
3. Metabolic imbalance. Too much activation of AMPK can disrupt glucose metabolism and contribute to insulin resistance and diabetes.
4. Hormonal Disruption: Too much AMPK activation can interfere with hormonal pathways. When our nutrients are too low or we’re overdoing fasting or exercise, we become less able to reproduce, and our hormones get out of balance.

Benefits and drawbacks of activating mTOR

mTOR (the growth pathway) is associated with robust health, muscularity and a strong immune system. When it’s activated, living organisms experience muscle growth and repair (muscle protein synthesis) and have increased resistance to disease.

Eating foods that are rich in protein and leucine — such as meat, eggs, fish and dairy products — is the primary way that people trigger the activation of mTOR.

On the downside, the overactivation of mTOR is associated with:

1. Accelerated aging: Cell growth is proliferation are important for tissue repair and development. But uncontrolled and sustained cell growth can lead to the accumulation of cellular damage over time.
2. Cellular senescence: mTOR activation has been linked to cellular senescence, a state in which cells lose their ability to divide and function properly.
3. Metabolic dysregulation, insulin resistance and obesity. mTOR activation can interfere with insulin signaling. When it’s overactivated, whether it’s from eating excess protein or excess carbohydrates and sugars, the result can be insulin resistance and an increased risk of type 2 diabetes.
4. Cancer. Too much activation of mTOR has been linked to the development and progression of certain types of cancer. mTOR promotes growth, and can promote the growth of cancer in the same way it supports the growth of healthy muscle tissue.
5. Impaired autophagy: AMPK promotes autophagy; mTOR inhibits it. Inhibition of autophagy due to mTOR overactivation can lead to the accumulation of damaged molecules and organelles, contributing to aging-related decline.

Both are important

In a nutshell, activating mTOR makes us stronger; activating AMPK may help us to live longer. One option people in the anti-aging community have been exploring is switching from one of these metabolic states to the other.

When AMPK is switched “on”, mTOR is usually switched “off”, and vise versa. Current research suggests that if we want to live long lives, AMPK should be activated most of the time.

Switching back and forth

mTOR can be thought of almost like a fire. It isn’t “bad”. It just shouldn’t be allowed to burn out of control. (See article: “mTOR as a Key Regulator in Maintaining Skeletal Muscle Mass“) But we need breaks from mTOR so that autophagy, apoptosis, and AMPK can become activated.

In his “The Switch“, James Clement suggests that it’s good to have AMPK activated (and mTOR switched off) about 3/4ths of the time. One way to do this would be to eat fewer calories. People who follow the CRON diet, “Caloric Restriction with Optimal Nutrition”, follow largely plant-based diets. (See article: “The ups and downs of caloric restriction and fasting: from molecular effects to clinical application“)

So we might try eating CRON diets nine months out of the year, as he suggests. then eat higher calorie, higher leucine, more animal-based diets the other three months.

We can make the switch weekly…

Another approach could be to segue between AMPK and mTOR once a week You might eat a plant based diet four or five days a week, then eat mostly animal foods the other two or three days.

…Or daily

Another approach would be to make the switch daily. This study suggests that when we eat a high protein, high leucine meal, mTOR is fully activated (which usually has the side effect of switching AMPK off) within 2 or 3 hours. (See study: Leucine-Enriched Nutrients and the Regulation of mTOR Signalling and Human Skeletal Muscle Protein Synthesis)

We know that AMPK is activated in the morning after fasting. So the transition from mTOR to AMPK activation and back again can be made at least once within a 24 hour period.

The trick is in the timing

Since AMPK is “on” when we wake up in the morning because in a fasted state (assuming that we didn’t get up in the middle of the night to gobble up some food) our actions shortly after waking can determine whether the AMPK activation continues or ends.

One way to continue it so would be to fast for a while after we get up, by postponing or skipping breakfast. If we don’t eat till noon, we’ll have extended our period of fasting, which moves us into autophagy, ketosis and AMPK activation, from 12 to 17 hours.

Another approach, which should in theory work just as well, would be to go ahead and eat in the morning, but choose foods which don’t activate mTOR. This is easy; we just need to eat foods very low in protein and carbohydrates. (Fats don’t trigger the activation of mTOR or AMPK; protein and carbs are what we need to be aware of).

For example…

• I got up at 6 a.m. this morning, had a tall glass of water, then a cup of coffee. Coffee is an AMPK activator and promotes autophagy. (I drink decaf because caffeine, even early in the morning, disrupts my sleep.) (Caffeime promotes autophagy, but so does decaffeinated coffee.)
• I took a supplement called AKG (alpha ketoglutarate) (in the form of plain AKG and Ca-AKG) along with my coffee.
• The research around AKG is somewhat contradictory, with some studies suggesting it slightly activates mTOR and others supporting the hypothesis that it activates AMPK. The latter seems to be winning out. According to an article called “Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK“, “Recent studies have shown that dietary AKG reduces mTOR pathway activation by inhibiting ATP synthase, thereby extending the lifespan of nematodes.”).
• A 2023 study states that “AKG inhibits ATP synthase, consequently reducing ATP level and oxygen consumption, which leads to indirect mTOR inhibition and autophagy activation. Regarding mTOR inhibition, AKG acts as a mimetic of caloric restriction. The geroprotective effect of AKG is linked with metabolic pathways modulation which is similar to the state of caloric restriction.”
• Two hours later, I took some NMN along with a fucoidan product called SIRT6 Activator, both of which support the AMPK pathway.
• I had a little food in the morning with my supplements (such as some olives or an egg yolk.
• I worked out around noon. After my workout, I drank some water with creatine and electrolytes.
• I plan to fast till 2 or 3 pm.

Timing your supplements

I took my NMN boosters and sirtuin activators along with it:

1. HealthThroughNutrition PQQ (20 mg)
2. Jarrow CoQ10 (200 mg)
3. DoNotAge NMN (1.5 grams)
4. DoNotAge NR (0.5 grams)
5. DoNotAge SIRT6 Activator (3 capsules)
6. DoNotAge Resveratrol (500 mg)
7. Parsley or apigenin (500 mg)

Some of them raise NMN; all of them are AMPK activators and support autophagy.

Then Switch on mTOR at Lunchtime

Around noon or 1 pm, I’ll have a meal with some plant and animal protein (leaning into animal-based foods for this meal). For example, I might have:

• A big green salad along with some lentil or bean soup along with some sardines, chicken or tuna.
• Scrambled eggs with sardines or anchovies and broccoli and tomatoes. seasoned with onions, garlic, rosemary,
• Grass-fed organic ground beef with broccoli and tomatoes and a big green salad on the side, seasoned with onions, garlic and rosemary.

All of these contain animal-based foods and are high in protein and rich in leucine, because I want to activate mTOR with this meal and shut off AMPK. I want the growth pathways activated. So I also take my testosterone boosters and hGH boosters with this meal.

Around 6 or 7, I might eat a meal that’s more plant-based and lower in animal-based foods, and take an AMPK activator such as berberine or benfotiamine along with it. Then I usually fast again till the next morning. So my AMPk and mTOR activation would look like this (blue is AMPK). If I wanted to dampen the mTOR activation further, I could choose more plant-based food, or just eat one meal a day. Then the image would be even more blue.

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