Ok mTOR. It’s this thing we hear a lot about in the longevity community.
And to me, it seems like inhibiting mTOR could be the single most impactful thing we can do for longevity. At least according to quite a bit of research.
In fact, inhibiting mTOR or food intake seem to be the two things we can do that work to extend the lifespan of many animals most reliably.
And of course we don’t really know if the same things happen in humans, because that can’t really be tested because we live too long.
And because no one will try to test something for as long as humans live, we never will have definitive knowledge of whether or not something works to extend human lifespan.
I suppose that some things are tested for quite a while in humans though: like the twenty-year-long 1990s metformin observational study. that recently came out. But that was just an observational study. But a long one and large one at that.
Even if someone said that they didn’t eat meat for say the second half of their life (40-80), we wouldn’t believe them. Someone would say: we don’t know what else you did that could cause you to live shorter or longer.
And that would be true.
Anyways, back to mTOR.
In this post I’m going to answer these questions that I have:
- How quickly does mTOR turn off and on?
- What causes it to turn on?
- How much meat do we have to eat to turn it on?
- If I’m undereating (say I’m dieting but not fasting), but eat a small amount of meat, do I activate it?.
- Can mTOR be “on” when AMPK is?
- Do we have to have it “on” to grow muscle?
- What are other ways besides eating meat that mTOR can be on?
- Is it true that running upregulates AMPK (but 20-30 minutes boosts testosterone) but lifting weights upregulates mTOR?
I’ve been wondering about this stuff for a long time, because MTOR seems to be really important. I mean every eukaryotic organism has this gene. Every mushroom, tree, bacteria, plant, animal. Everything.
Except in non-mammals it’s just called TOR, because the “m” in “mTOR” stands for mammalian (but I guess that is turning into “mechanistic” now).
What is mTOR?
Ok, I won’t go too far into this, but I do want to give readers who aren’t overly familiar an overview of what mTOR actually is.
mTOR is a protein that all eukaryotes have. So basically every plant, animal and fungi.
It’s a protein that coordinates cell growth based on environmental conditions.
It basically is one gene or one protein that turns “on” when we have lots of nutrients floating around (and other conditions that are requisite for cell growth) in our system. And it turns off when we don’t have lots of nutrients.
There is a network of proteins that work together to signal cells to divide and/or grow, among other things.
Think about good times: when we have lots of food our bodies decide to grow; when there isn’t (or wasn’t rather), our bodies would focus on survival and not cell growth.
Cell growth wouldn’t have been possible anyways, because lots of stuff is required for cells to divide and grow.
The specific nutrient(s) that seem to really turn on mTOR the most are amino acids. And the amino acid that affects it the most is leucine[citation needed].
mTOR lifespan extension research in non-humans
Ok, here is a list of research that shows that inhibiting mTOR can increase lifespan in various non-human organisms:
- TOR deficiency in C. Elegans (worms) more than doubles its natural lifespan (link)
– Fully depleting TOR causes C. Elegans to live on average 25 days instead of 10 days - Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
– Rats fed rapamycin at an old age (equivalent to human age of 60 years) extended their lifespan by 14% for females and 9% for males at three test sites (link) [editor’s note: Rapaymcin is a drug that inhibits mTOR, in case you didn’t know] - Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction
– “Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females)“
– (link)
Does just the presence of ”nutrients” upregulate it or is mechanical stimulation also required?
After reading tons of papers and watching super detailed videos like this one with Dr. Sabatini, it does seem that just the presence of nutrients tells our bodies to grow (this is a gross oversimplifciation).
Those nutrients could be amino acids or glucose. They do not have to be amino acids[citation needed].
Does inhibiting mTOR result in increased lifespan in every species?
People always say “it worked in mice|flies|yeast, but will it work in humans”? And this is a fair question.
So I was wondering if inhibiting mTOR works in every species this has been tested in. I would certainly feel more confident that it does work in humans (though very importantly, we already have quite good evidence that yes, it is doing something in humans as well).
So basically I have searched for research where inhibiting mTOR does not increase lifespan in this section.
And according to Matt Kaeberlein, it does basically work everywhere it is tested, in every species.
What is mTOR?
Ok, first let’s look at what mTOR is.
I’m not going to spend much time on things that you probably already know about or stuff from Wikipedia.
I really want to dig in to the research and understand this protein, so I can use what I learn writing this artcile in my daily life to hopefully live a longer, healthier life.
First off, mTOR stands for “mammalian target of rapamycin”. So mTOR is named the way it is because a particular medicine affects it. That medicine is rapamycin, which is the best way we know of to inhibit (whatever that means) mTOR.
Ok, so it’s a kinase that is encoded by the mTOR gene.
I’m repeating some stuff straight from Wikipedia to layout a foundation and just sort of know what we’re working with here. I really want to dig deep and understand what this thing is, since it seems so important.
I mean mTOR could be THE thing we’ve been looking for. Or one of the things that we can affect later on.
Maybe if we turn off mTOR and a few other things like it (yet to be discovered), we can double lifespan? Maybe. I mean aging is programmed in some way.
Ok back to what mTOR is.
Wikipedia says this:
mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes.
https://en.wikipedia.org/wiki/MTOR
Ok, that’s pretty vague though. It “regulates different cellular processes”. That doesn’t tell us much.
The next sentence goes on to say:
In particular, as a core component of both complexes, mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription.
Ok, now we’re cooking with gas. This provides us with a little bit more to work with and delve into.
Cell growth, proliferation, motility, survival, protein synthesis, autophagy and transcription seem like pretty important things. I’m going to explore each of these things. Maybe not motility, but definitely the other things.
Evidence that mTOR matters
So from the above, it seems that the amount of growth and the speed of that growth matters.
Let’s go over some of the evidence that proves that mTOR matters.
mTOR is found not only in humans and other mammals but also in:
- Chimpanzees
- Oppossums
- Chickens
- Cows
- Fruit flies
- Frogs
- Zebrafish
- Worms
- Yeast
- The malaria mosquito
- Rice
- Barley
- Sea squirts (did not know what this is)
In fact, if I kept writing out this list, the list would stretch for a long way, because TOR (mTOR is mammal-specific TOR so TOR and mTOR are basically synonyms) is found in all eukaryotic organisms.
There are 8.7 million eukaryotic species, and each one takes up roughly one centimeter on my screen. That makes the list of all species with the TOR gene 87 kilometers long. That’s how highly conserved and important TOR is.
The more widely prevalent a gene is, the older the most recent common ancestor was.
In fact, TOR is so old that it is older than the LECA, or Last Eukaryote Common Ancestor. This means that it was present in some single celled organisms.
Why should we care about size and growth rates?
At a high level, one of the things that mTOR and rapamycin seem to pertain to is cell growth.
We know that growth rates and absolute amounts of growth affect how long we live.
- Smaller people live longer
- The taller different ethnic groups in California are, the more health problems they have
- Source
- People who reach puberty earlier live shorter lives
- Some people with dwarfism have no diabetes and cancer (this isn’t directly about growth but does show that the absolute amount of growth matters)
- The inability to make IGF-1 is the cause of Laron dwarfism, which completely prevents cancer and diabetes
- “Shorter, smaller bodies have lower death rates and fewer diet-related chronic diseases“
- Smaller individuals within many species live longer
Evolution has programmed each species to live a certain lifespan
We know that different species live different lengths of time. There’s no single optimal timespan to live. The optimal lifespan is determined by your environment.
One species of jellyfish is immortal. Greenland sharks can live 500 years. American deer live 5-7 years.
So evolution has optimized each species to its environment over the course of time. It’s said “you deer, you are more likely to pass on your genes if you live 7 years”.
And you ocean-faring fish, because you live in a larger environment where you can spread your genes, you should live longer (for your body size) than land-bound animals.
If you think about it, since we know that evolution and each species genes do “tell” each species how long to live, evolution needs to figure out a way to regulate lifespan.
And it needs to do that in a constant way. You want each individual living roughly on average the same length of time.
Or maybe you don’t care about the specifics of the individual, but you do care about the average lifespan. Evolution says when individuals live this length of time, on average, the group has the highest chance of survival.
Evolutionarily speaking, a food-sensing gene that regulates lifespan makes sense
If you believe that evolution has programmed our genes to cause each specifies to live roughly the same period of time, how are you going to do that in a simple way (not that our bodies are simple, but simpler is better)?
Having a gene (or genes) that are affected by food intake is a fairly simple way to keep lifespan a similar duration across individuals.
Since we eat approximately the same amount of food (per unit of mass), having a gene that is affected by food would be a good way to do this.
Humans’ metabolisms or resting energy expenditure are roughly the same. And while some of us are more efficient than others (just like we vary in some degree on almost all factors), we do burn roughly the same amount of calories.
And burning a similar number of calories means we have to eat a similar amount of food. This means that quantity of food eaten would be a very simple way for evolution to affect our lifespans.
But it’s not just that we eat a similar amount of food that makes this an obvious choice for evolution.
The fact that the more food an individual has eaten, the better the life they have likely had and the greater the chances are that they have been able to reproduce is likely true.
This is true even today with birth rates having dipped when times are tough.
If you are very hungry, are you thinking about sex? No. Are you thinking about reproducing? No. Especially not a million years ago.
So if a human underwent a very dry or cold season when there were fewer animals and plants to eat a million years ago, it’s less likely they would reproduce during and around that time period. And if they did reproduce, the offspring are less likely to survive.
So our genes having this sort of aging on-off switch based on how much we eat makes a lot of sense, from an evolutionary perspective.
This begs the question of whether or not abstaining from sex could also be another factor. It would be simple to measure: how many times has a man ejaculated in his life and how many offspring has a woman had?
Do women with more kids die earlier or later? That should be a known fact and pretty easy to look up. For men seems like it might be a bit harder to track how many times they’ve ejaculated.
Off the topic of this post (or is it?) but it seems that having kids leads to slightly longer lifetimes, at least for people born in Sweden around 1900.
But this Nature article says that having sons did shorten the lifespan of some Finnish mothers (starting a few hundred years ago). I’d like to look at some more “natural” living hunter-gatherer society data for this.
What is mTORC2?
First off,
mTORC is a protein complex formed by serine/threonine kinase mTOR.
https://en.wikipedia.org/wiki/MTORC2
mTOR affects two things that are called mTORC1 and mTORC2. mTORC1 is the “complex” that “appears to provide most of the beneficial effects of rapamycin”.
So we’re going to focus on mTORC2 (if you click that it will take you to this page where I explain mTORC2 in hopefully an understandable way).
What does mTOR do when it’s “on”?
So we’ve established that mTOR seems to be quite important.
It’s an ancient gene, going all the way back to the Last Eukaryote Common Ancestor. This was the first cell that gave rise to all eukaryotes.