Hey, Lance here. And today, we’re going to be talking about the mTOR pathway.
Keeping this pathway under control is one of the essential strategies to turning back the clock
and living a radically longer and healthier life.
So, stay tuned if you’d like to learn my game plan for accomplishing that.
The topic of today’s video is the mTOR pathway, one of the Nutrient Sensing pathways.
We’re going to be addressing the impact that it has on aging
and the importance of keeping both the mTOR pathway and the AMPK pathway in balance.
And we’ll also cover some strategies for doing that, and some remaining questions that I have.
The term “mTOR” is an acronym that stands for either “mechanistic target of rapamycin”
or “mammalian target of rapamycin,”
and it’s an enzyme that’s encoded by the mTOR gene.
This particular enzyme is a kinase,
and these are enzymes that catalyze the transfer of a phosphate group
from high-energy, phosphate-donating molecules to a specific substrate.
The origination of this pathway started with a molecule that was discovered in a soil sample from Easter Island,
known to locals as Rapa Nui.
This molecule was found to have potent anti-fungal activity,
so it was named rapamycin, a combination of the name of it’s original source, Rapa Nui,
and mycin, because of it’s anti fungal activity.
Early testing revealed that rapamycin also had potent immunosuppressive and anti-cancer activity.
About 20 years later, a new discovery revealed that rapamycin targeted a specific enzyme in mammalian tissue.
So now, this enzyme, and the pathway that it activates,
is called the mechanistic, or mammalian, target of rapamycin…or the mTOR pathway.
OK, that’s probably enough history. The real questions is: what is it?
What does it do? And why’s it so important to the aging process?
Whenever there’s plenty of calories and nutrition available, primarily protein,
signals go out that tell the body that all is well, we’ve got plenty of food so that we can be very active,
and that we’re going to need lots of muscle and we’re gonna consume lots of energy.
The mitochondria crank up their working capacity, and ATP production goes up.
Cells divide more, and we poised for both tissue growth and repair.
mTOR is the pathway that senses this abundance of nutrition
and activates the mechanisms required for all of this growth and repair.
However, when the food supply is reduced and the caloric intake is restricted,
activation of the mTOR pathway is inhibited.
But more on that later.
First, let’s get into the science.
The mTOR pathway is one of four pathways that control the metabolism.
MTOR and the IIS pathway, also known as the “Insulin and Insulin-like Growth Factor 1 Pathway”,
are both anabolic pathways.
The other 2 pathways are the SIRT and the AMPK pathways, both of which are catabolic pathways.
The mTOR pathway regulates cell growth, proliferation, motility, and survival,
it regulates protein synthesis, autophagy and transcription.
And the pathway is super complex.
Here’s one diagram of all of the different signaling pathways that make up the mTOR pathway.
Here’s another. Way too complicated for me.
OK, so the mTOR pathway include two distinct complexes: mTORC-1, or mTOR Complex 1,
and mTORC-2.
The mTOR pathway acts as a central hub, integrating signals from upstream pathways,
including growth factors, such as IFG-1 and IGF-2, insulin and amino acids.
It also plays a role in sensing cellular nutrients, oxygen and energy levels.
So this pathway acts as a molecular switch to regulate cellular growth and proliferation in response to nutrients.
But, having all of this growth and higher energy levels…comes at a price.
Activating the mTOR pathway has both benefits and costs…but so does inhibiting that pathway.
mTOR increases energy production and performance, but it produces junk products in the process.
Now, autophagy, which is the recycling of cellular material,
is the process that breaks down these junk products and recycles them.
But autophagy only kicks in when the mTOR pathway is inhibited.
In other words, the cleaning crew doesn’t come in until after the workday is done.
But here’s the thing: while activating the mTOR pathway is great for growth and energy,
it turns out that, because of all the junk products created, it’s really bad for longevity.
Apparently, tissue growth and extended lifespans are mutually exclusive.
You can have one, or the other. But not both.
Think of the phrase “Live Fast, Die Young”.
Animals that grow very quickly, like mice, insects and worms, have very short lifespans.
Animals that grow very slowly, like whales and elephants, have very long lifespans.
So big, slow-growing animals live a lot longer than small, very fast-growing animals.
However, within a species, it’s just the opposite.
Bigger animals have shorter lifespans than small ones.
An animal that grows larger in the same amount of time will not live as long as an animal that grows less.
Big dogs have drastically shorter lifespans than small dogs.
And the mTOR pathway is one of the reasons why.
Too much mTOR pathway activation can also contribute to a large number of chronic diseases
like cancer, obesity, type 2 diabetes, and neurodegeneration.
It’s association with cancer may come because it promotes angiogenesis,
which is the process that forms new blood vessels from pre-existing ones…and this helps cancer to grow.
Inhibiting the mTOR pathway improves insulin sensitivity and promotes autophagy.
Remember, autophagy is only activated when mTOR is inhibited.
There’s another enzyme called AMPK, which is also a kinase.
Activating AMPK both stimulates autophagy and inhibits mTOR.
I did an earlier video on AMPK, and you can access that video by clicking on the card up here.
I’ll also put a link to that in the description below.
The thing that I didn’t mention in that video is that you can activate either the AMPK pathway,
or the mTOR pathway, but not both.
Activating the AMPK pathway shuts down the mTOR pathway, and kicks autophagy into overdrive.
But there’s another way to shut down the mTOR pathway.
Remember rapamycin, the pharmaceutical that targets this pathway?
In addition to being a potent anti-fungal, immunosuppressive and anti-cancer drug,
it turns out that rapamycin inhibits the mTOR pathway.
It prevents it from activating.
Apparently, the drug is thought to work by making cells think that there aren’t very many nutrients available,
and so they go into survival mode and don’t proliferate as much.
Just as they would during calorie restriction.
In numerous studies, rapamycin has extended lifespans in mice, sometimes by as much as 60%.
In another study with dogs,
rapamycin produced similar cardiovascular benefits in large dogs as those seen in mice.
The same researchers have a second, longer study ongoing,
and it examines the dog’s heart and cognitive health more closely,
in the hopes of extending the dog’s life…and eventually, mankind’s.
But here’s the thing.
Not all mTOR activation is bad.
Activating the mTOR pathway can do a lot of good.
It’s required to heal wounds. For growing muscles. For more energy.
And as aging adults, we need those things.
As we get older, sarcopenia, or the loss of muscle mass, becomes more and more prevalent.
We need to stave off that loss of muscle mass and we need to grow new muscle, if possible.
So we need to consume larger amounts of protein, in order to do just that.
And an abundance of protein activates the mTOR pathway.
So we need to find a balance between activating and inhibiting the mTOR pathway.
Now, rapamycin has a really long half-life,
which is the amount of time it take your body to clear out half of the drug.
With rapamycin, it’s between 62 and 82 hours in humans.
That means that after up to 3.5 days, only half of the rapamycin has been cleared.
And I think that I’d want to activate the mTOR pathway more frequently than that.
For that reason, I feel that taking something like rapamycin isn’t really the answer I’m looking for.
Because sometimes we need to activate the mTOR pathway, particularly as aging adults.
And having that much rapamycin in our systems prevents that.
We need to appropriately cycle between periods when the mTOR pathway is activated,
and we’re growing new muscle tissue, we’re healing, and we’re boosting our energy production…
and periods when the mTOR pathway is inhibited
and instead, the process of autophagy is activated, and we’re clearing out toxic cellular waste.
And the key here seems to be over-activation.
From what I’ve read, it seems that over-activation is far worse that adequate activation.
One other thing.
Although the mTOR pathway is activated in the presence of amino acids,
recent research seems to point to the amino acid methionine as the one the has a primary effect.
Studies have been done that demonstrate that a methionine restricted diet
is effective in inhibiting the activation of the mTOR pathway.
However, personally, I don’t see myself doing that because methionine is present in most of the proteins that I eat.
Like lean beef, salmon, egg whites, tuna and most nuts…except macadamia nuts.
Macadamia nuts are really low in methionine.
So, if I understand this correctly,
it seems that mTOR is activated by an abundance of nutrients, particularly protein.
However, remember that the AMPK pathway is activated by exercise or fasting.
And activating the AMPK pathway inhibits the mTOR pathway.
So, in theory at least, this seems to give us a clue in how to balance the AMPK and the mTOR pathways.
Since I always exercise in a fasted state,
I kinda feel like this probably activates the AMPK pathway and shuts down mTOR.
During my feeding window, I don’t really consume a lot of calories,
and most of what I eat is nuts and veggies, with small amounts of fish or chicken.
So, while I feel that this probably activates the mTOR pathway, I don’t feel that it over-activates it.
But let’s say that instead I do a really heavy set of lifting weights,
followed at some point by consuming an extra large amount of protein during my feeding window.
This, in theory, should really help with the recovery and build new muscle tissue
by super-charging that mTOR pathway,
along with the tissue-building and repairing processes that I’m looking for, and shut down the AMPK pathway.
Then, once recovery is finished, I can re-activate AMPK and turn off mTOR by going into another fast.
But here’s the thing I’m not sure of.
And that's the timing.
During the muscle-building and repairing phase of recovery,
I want a lot of protein available to fuel that process, and I want mTOR turned on to activate that process.
I don’t want to saturate my system with a lot of protein all the time,
because that would keep my mTOR pathway activated all the time.
I only want the extra protein when I need it.
The rest of the time, I want my AMPK pathway activated,
and I want autophagy clearing out the junk products created by tissue building.
Now, I’ve read that the muscle-building and repair process occurs at the very end of the recovery process.
My problem is that I’m not sure exactly when that happens.
I’ve read that you should eat a lot of protein within 60- to 90 minutes of finishing a heavy workout.
But I’ve also read various articles that state that the recovery process can take anywhere between 36 hours and a week.
So, I just don’t know.
I’d love it if there was a way to know definitively when the actual tissue-building phase of recovery happens.
If any of you guys have an answer to this, leave me a comment.
I’d love to hear what you guys think.
Now, unfortunately, there’s no way to measure how any of this is working, that I know of.
I’ve heard of no way to know when mTOR is activated and when AMPK is activated.
I think I can assume that if I’m increasing strength and muscle mass, then mTOR is being activated…
and if I’m improving my cardiovascular fitness and my mitochondrial health, then AMPK is being activated.
But the only way to know for sure is to check-in in about 10 or 20 years and see how this old body is holding up.
So, for now, I think I’ll stick with this program..
at least until something better comes along as the result of the continuing research into aging.
Hope you enjoyed this video.
If you’d like to learn more about other nutrient-sensing pathways, check out this playlist.
That’s it for me, I’m outta here.
Catchya next time.