In the past few videos in this series, we’ve talked about the AMPK pathway, the mTOR pathway.
We’ve talked about autophagy and we’ve talked about fasting.
This is the video where I pull it all together and explain how I balance mTOR with AMPK.
So, stay tuned.
For a long time now, I’ve been struggling with how to balance the AMPK pathway with the mTOR pathway.
Some studies have been published that have demonstrated that taking rapamycin can extend lifespans, at least in mice.
Or maybe it was flatworms.
The point is, it’s believed that rapamycin shuts down the mTOR pathway,
which is thought to be antagonistic towards extending the human lifespan.
So rapamycin is thought to be one of the primary longevity drugs, along with metformin and datasinib.
Now I don’t think it should be.
And I also believe that the mTOR pathway has gotten a bad rap.
I think that activating the mTOR pathway on a regular basis is critical to living a long and healthy life.
It all starts with a theory of aging that I subscribe to and that is promoted by David Sinclair,
one of the top researchers in the field of longevity.
Now this theory holds that way, way back in our evolution, biology developed two distinct states.
One was a fed state, in which nutrients were plentiful.
The other state was a starvation state, in which nutrients were either scarce or none existent.
Now remember, we’re talking about cells, not entire organisms.
This evolutionary stage was developed when all organisms were at the single-cell stage.
When nutrients were plentiful, cells grew and reproduced.
But when nutrients were scarce, a molecular switch was thrown and cells stopped growing and reproducing.
Instead, they turned to repair and maintenance. Repairs were made to the genome and to the epigenome.
This makes sense, because you don’t want cells reproducing and passing on faulty DNA.
When nutrients are plentiful, particularly amino acids, the mTOR pathway was activated.
mTOR is required for muscle synthesis and tissue growth. It’s required for wound healing.
When mTOR is activated, cells are active and motile.
But when nutrients are scarce, AMPK is activated, which shuts down mTOR.
A lot of good things happen when AMPK is activated.
Cells don’t make or store fat, instead burning it for energy.
Blood sugar levels drop and insulin sensitivity is increased.
Autophagy is triggered, recycling and renewing cellular components.
It also triggers mitochondrial biogenesis, the creation of new mitochondria.
It stimulates the production of SIRT1 and it’s critical to the immune system.
It also inhibits production of nuclear factor-kappaB, a pro-inflammatory pathway.
You see, both AMPK and mTOR are nutrient-sensing pathways, and they’re antagonistic to one another.
Only one pathway can be activated at a time, and activating AMPK shuts down the mTOR pathway.
Now, both pathways have benefits, and both are crucial to a long and healthy life.
Now I know, you may have heard that activating mTOR does NOT promote longevity,
that it’s shutting mTOR down with something like rapamycin that promotes longevity.
But I don’t agree with that theory, and I’m not alone.
One of the aspects of aging that correlates most strongly with a diminishing healthspan is frailty and loss of strength due to sarcopenia,
or age-related loss of muscle mass.
And the best way to avoid this is to build up your muscle mass with exercise, which requires an activated mTOR pathway.
But you need to balance this with an activated AMPK pathway.
One of the reasons that I suspect that mTOR gets such a bad rap in the longevity community is this:
until recently, I don’t think that I have ever fully activated the AMPK pathway in my life.
We live in a time of such abundant food that there is a constant stream of excess nutrients flowing through our bodies.
One of the factors that is most strongly associated with an activated AMPK pathway is autophagy.
And to launch autophagy requires fasting for a minimum of 24 hours,
and fasting for 48 to 72 hours is required to fully activate the highest levels of autophagy.
Now, up until about 10 years ago, I had never gone longer than about 12 hours without food,
and that only happened when I slept.
I had never done an extended fast until about 4 or 5 months ago.
So I feel that I’ve lived most of my life in a state of activated mTOR,
with an abundance of amino acids present in my blood stream.
And that means that I’ve almost never activated the AMPK pathway.
And that’s not good. That’s when most of the repair processes are triggered.
Think of it like this:
any time you have high levels of anything present in your body for an extended period of time…
like all my life, that pathway get desensitized.
If you consistently have high levels of insulin, for example, you develop insulin insensitivity.
And you body doesn’t respond to insulin like it’s supposed to. And you develop diabetes.
Same with mTOR.
If your baseline mTOR activity is high, then when you do something to raise it,
like exercising in a presence of high levels of protein,
you don’t raise it that much and you body doesn’t respond by growing new muscles nearly as well as it should.
So, I feel that it’s really important to balance mTOR with AMPK. You need both.
You need periods where you’re growing and repairing muscle tissue,
but you also need periods where you’re recycling cellular components and repairing damaged DNA and the epigenome.
So, how do you do that?
To be honest, I’m not really sure.
I’ve scoured the sources and all I’ve found is contradictory evidence.
So I’ve had to develop a plan of my own. Here’s what I do.
I cycle periods where I concentrate on activating mTOR with periods where I strive to activate AMPK and shut down mTOR.
And for me, right now, these periods are about 3 to 5 months long.
So, why do I cycle, and why did I choose 3 to 5 months as the length of a cycle,
rather than, say 3 or 4 days?
It’s because of the way that we have evolved.
Evolution has occurred the way that it has because our ancestors were subject to periods that cycled.
Periods where nutrients were plentiful and periods were nutrients were scarce.
Sometime these periods could cycle on a basis of a few days to a few weeks.
But more often, they cycled with the seasons, and these cycles could last for months.
Our ancestors had periods when game and gathered food was abundant.
They were hunting down game and gathering large stores of plants, seeds, nuts, berries and roots.
These were periods of high-calorie activity.
They consumed a lot of calories and they burned through a lot of calories during these periods.
These were periods where they were frequently in anabolic states.
Their bodies needed to ramp up to be successful during these periods of high activity.
But they also went through periods when food was scarce or non-existent.
Like during winter, or during a drought.
During these periods, there was no game to chase, no plants to gather.
So they hunkered down and tried to burn as few calories as possible. Activity slowed way down.
And during these periods they would have been in a catabolic state.
They lost weight, they burned through their fat stores.
But they also underwent cellular repair during these periods
This is the environment that our bodies evolved to thrive in.
If we want to build a good longevity foundation, we need to choose a lifestyle that mimics the environment that we evolved in.
We are genetically wired to do the best we can in this environment.
The fast-food, sedentary lifestyle that most of the world choses to live is the antithesis of that environment.
We have lots of nutrients available all the time, which eliminates the periods of scarcity that we need for cellular repair.
But we don’t have an accompanying high level of activity,
so we don’t receive the improvements in strength and endurance that derive from abundance.
Because we only have one, constant on-going period that is a weird combination of both of our ancestor’s cycles,
we don’t get any of the benefits of either.
Because of the way we evolved, we need both periods.
We need a period of lower activity and nutrients scarcity to tear our bodies down and recycle and repair cellular processes.
And we need a period of abundant nutrients and high activity to build up our bodies back up.
It’s this tearing down and building back up, on a regular cyclical basis that we evolved to cope with.
That’s why I try to have a cycle that lasts for about 3 to 5 months.
During one cycle,
let’s call it the winter or drought cycle when nutrients were scarce and our ancestors were hunkering down and trying to stave off hunger,
that's the cycle in which weight loss happens.
I do a lot of fasting, I do keto, I’m not trying to bulk up.
I do more HIIT, and I’m hopefully doing a lot of cellular repairs and recycling.
During the other cycle, the cycle when nutrients were abundant and our ancestors were very active,
chasing down game and gathering food, is the cycle when I’m trying to bulk up and grow new tissue.
During this cycle I up my protein intake, I don’t due extended fasts, I cycle my IF, I do more resistance training and less HIIT.
Now, here’s the thing. I call these two cycles my anabolic cycle and my catabolic cycle.
But my anabolic cycle isn’t just anabolic. There are periods where I’m in a slightly catabolic state.
And my catabolic periods are just the same, with periods where I’m slightly anabolic.
But my goal during the anabolic state is an anabolic one.
I’m trying to build up my muscle tissue.
And my goal during the catabolic cycle is to tear down fat tissue and do cellular repair.
Because when I’m in an anabolic state, I build up muscle tissue, but I also build up fat tissue.
And when I’m in a catabolic state, I tear down fat tissue but I also tear down a small amount of muscle tissue.
So my goals here are to build up more muscle in the anabolic state than I tear down in the catabolic state,
and to tear down more fat tissue in the catabolic state than I build up in the anabolic state.
I go through a 3 to 5 month period where I try to bulk up.
My goal during this period is to build muscle mass.
And the two primary tool that I use to do this is nutrition and exercise.
I eat a modified ketogenic diet, which is still really low in carbs, but has more protein,
more amino acids…particularly leucine and methionine.
I supplement my protein intake with PerfectAmino, which is a formulation of essential amino acids.
I also take HMB, which stand for hydroxymethylbutyrate, combined with vitamin D.
HMB is a metabolite of leucine and taking it can improve protein synthesis.
Taking it with vitamin D can supercharge it’s ability to build muscles.
I also tend not to do as much intermittent fasting.
If I eat prior to working out, I find that I have more energy and can do a more intense workout.
And when I work out, I do less high intensity interval training and more weight lifting.
And I lift heavy. I do intense workouts. I lift as much as I can and I lift to failure.
After around 3 to 5 months of doing that, I shift to activating AMPK.
During this period, I move to a full ketogenic diet.
Very low carbs, relatively low protein and lots of healthy fats. And I do IF full time.
But I also do an extended fast once a month.
And I try to do that fast for as long as I can, three days at least and a week if I can pull it off.
I’m really trying to experience autophagy for as long as possible.
Then, when I end the fast, that’s the only time I do a lot of protein, usually in the form of PerfectAmino.
The reason for this is that during a fast, the body recycles a lot of cellular waste
and is primed for making repairs when the fast ends.
So, by having a surplus of amino acids present in my bloodstream,
I’m primed for making those repairs and building back any muscle tissue I might have lost during the fast.
But I only do this for a couple of days.
Also during this period, I transition to doing more HIIT 3 times a week,
and I do my workouts in a fasted state.
I do less lifting and now my resistance training focuses more on bodyweight training and mobility training.
I also do a session of nitric oxide dumps 3 times a day, 7 days a week.
Finally, this is when I do senolytics.
Since the whole purpose of taking senolytics is to remove senescent cells, this feels like part of the housecleaning that I do when AMPK is activated.
There seems to be a tendency or a movement within the longevity movement to want to activate AMPK
and suppress mTOR as much as possible. but I don't necessarily agree.
Now I know that there are a number of studies that suggest that giving mice a steady diet of rapamycin can extend their lifespans.
I know that rapamycin is considered to be one of the primary longevity drugs,
along with metformin and dasatinib, but I don’t take it, and I’ll tell you why.
First off, it has a really long half life.
It takes between 62 and 82 hours to clear half of the drug from your system.
But the primary reason that I don’t take it is because if suppresses mTOR universally.
It suppresses mTOR in every tissue in your body.
Most people don’t realize that when you exercise in a fed state, while it activates mTOR in skeletal muscle tissue,
it actually lowers mTOR activation in other tissues, like in fat and organ tissue, like the liver.
Rapamycin also decreases insulin sensitivity, it can cause muscle wasting and can impair muscle regeneration after a workout.
Finally, mTOR is absolutely essential to the immune system, but rapamycin suppresses the immune system.
It was developed to shut down the immune system to keep organ transplant recipients from rejecting their transplants.
And I think that we can all agree that a healthy immune system is key is you want to live a long time.
So, for all these reasons, I personally stay away from rapamycin.
I think a much better approach is to selectively suppress mTOR on an as needed basis, rather than just universally shut it down.
Now, I want you guys to remember that I’m not a researcher or a scientist.
I’m just a guy who wants to live long time and stay healthy, so I read a lot on the subject.
But I’m not a doctor and I’ll admit, a lot of the literature is way above my pay grade,
and this particular topic is controversial.
Some scientists and researchers have published studies that agree with my opinion, and that’s all it is, an opinion.
And some have taken the other side.
Which means that nobody really knows, and you need to decide for yourself and act accordingly.
OK, that’s it for balancing the AMPK and mTOR pathways.
If you enjoyed this video and would like to watch the rest of the videos in this series,
check out this playlist. And I’ll catch you guys…next time.