Inhibiting mTOR for longevity is perfect, well almost.
A look into how mTOR inhibition can be improved and simulations that I created of mTOR.
From the beginning of time, we humans have dreamed of immortality. We wanted to bring the stories of Hercules to life in ourselves and live forever. So, why didn’t the discovery of the anti-aging properties of mTOR inhibitors shake the world?
Rapamycin, an anti-aging drug comes with a lot of uncertainty. Many of the side effects are irreversible, which sounds pretty scary.
But hey, medical and technological advancements always have some risk, right? Rapamycin has got some considerable risks, however this article explains the strategies that can be implemented to reduce this risk, and make the drug as well as the overall process of inhibiting mTOR safe enough for common public use.
Backtracking to the Beginning
After learning in depth about mTOR and its complexes, I wanted to go even deeper. So I simulated the different complexes of mTOR, using PyMOL. I used Protein Data Bank files and highlighted different important regions using different colours to help explain the functions. I focused on demonstrating the complexity of the protein, and later go on to explain how it can be better inhibited.
First thing’s first: What even is mTOR?
mTOR = Mammalian target of Rapamycin.
So quite simply, it’s the target of Rapamycin, a drug which inhibits mTOR.
Now, not so simply:
Yeah.. it’s pretty complicated. Not to worry though, we will be focusing in on only mTORC1 and mTORC2 in this article.
mTOR is the catalytic subunit of two protein complexes, mTORC1 and mTORC2 and is the major regulator of growth in animals and controls most anabolic and catabolic processes in response to nutrients and nutrient-induced signals, like insulin. It plays major roles in physiology, metabolism, and aging.
mTORC1
This complex is composed of mTOR itself, regulatory-associated protein of mTOR (raptor), mammalian lethal with SEC13 protein 8 (MLST8), PRAS40 and DEPTOR.
mTORC1 is activated through growth factors stimulation, increase in amino acid levels and cellular energy status. Autophagy and metabolic processes are also stimulated by mTORC1 action. It was demonstrated that mTORC1 signalling is strongly implicated in the aging process of diverse organisms.
mTORC1’s job is to activate movement of proteins. For cells to grow and proliferate by creating more proteins, the cells must have the resources available for protein production. You can’t get energy from non-existent food!
Therefore, for protein production and mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation and autophagy to begin.
mTORC2
mTOR Complex 2 is a rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival.
The catalytic mTOR subunit, DEPTOR, and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. RICTOR, mSIN1, and Protor1/2 can only be found mTORC2.
As you can see, mTORC2 doesn’t really have an autophagy property, thus why it is typically not looked at for lifespan-extending purposes. Regardless, it does indeed do some pretty cool things! Though less understood than mTORC1, mTORC2 responds to growth factors and modulates cell metabolism and cell survival, thanks to its activation of the survival kinase Ak.
Activation and Inhibition
mTOR is a pathway which is essentially the master controller of protein synthesis. When there’s a lot of if, it promotes growth. Sounds good right? Not always, too much mTOR activation also promotes the growth of cancer too.
On the flip side, when it’s low, the pathway changes and is designed for repair and maintenance of the body. Therefore, stimulating autophagy. (This is good).
Stimulated autophagy has anti-aging effects so obviously, we want to decrease mTOR if we have lifespan-extending intentions.
Inhibiting mTOR
It has been proven in multiple model organisms that inhibiting mTOR does indeed increase life and health spans.
It was first proved in budding yeast.
Yeast?
That’s right, the ingredient we bake with had its lifespan extended.
Two aging paradigms have been described in yeast:
- Chronological aging: The length of time that a yeast cell can survive in a nondividing state.
- Replicative aging: The number of daughter cells a mother cell can produce before the irreversible cell cycle arrest.
To create long-living yeast, Fabrizio isolated a mutation in SCH9, which is a TORC1 target in yeast. Later studies showed that the deletions of either SCH9 or TOR1 (which function only in yeast mTORC1), is enough to extend both of the aging paradigms mentioned above!
Okay, but yeast is still very far away from humans. Scientists got one step even closer, extending the lifespan of fruit flies!
This is insane. Proven increased lifespan in living organisms?
Okay, when is our turn?
Where’s our spot in line for lifespan extension?
Far, far at the back.
Here’s the catch: Rapamycin is only effective for older mice, and by older people I mean old. Extending the lifespan is great regardless, but it seems a bit fruitless when health span has already reached its worst.
Also, complete inhibition of mTOR is not optimal for human adults, they still need activation of the mTOR pathway to heal wounds, growing muscles and make energy!
As we get older, sarcopenia, muscle loss becomes more and more prevalent. With the constant inhibition of mTOR, this becomes difficult. This is a problem with the overall function of the mTOR pathway. You can’t inhibit and activate something at the same time, leaving scientists in a bit of dilemma, drug development-wise.
Rapamycin has a few side-effects too:
- Decreased kidney function
- Anemia
- Decreased blood platelets
And these are only a few of the common, severe ones.
The Recipe for Inhibition Improvement
Creating an optimal internal environment
Rapamycin slows aging, extends life span, and prevents age-related diseases, like diabetes and cancer. What if we could 2x the efficiency of the drug?
Fasting inhibits mTOR as the mitochondria is not being put into use, activating the pathway. So, what if you could fast for long enough, already inhibiting the pathway before you take Rapamycin? Rather than just the effect of the drug, you could get a 2x or even 5x gain.
Pairing Rapamycin and intermittent fasting is something scientists should look into more, as it may be a way to improve the results of mTOR inhibiting exponentially.
Other Inhibitors
New inhibitors are being discovered and developed each passing day, looking at the possible variations of Rapamycin is an area worth researching.
A few variations already exist:
The key issue with Rapamycin is the age at which it is effective. Scientists do not actually know why the drug only shows results in older individuals, much more research is needed.
Taking the step towards longevity in humans
Health span is broadly defined as the period of life spent free of chronic disease and disability, however before interventions like Rapamycin can be seriously considered in the context of human aging, we need a better understanding of their impact on overall health during aging.
A major barrier to this is the lack of standardized biomarkers of aging, aging rate, or healthy aging in model systems. Even though there is large consensus that Rapamycin can extend lifespan in simple eukaryotes and mice, there is a big question mark on whether Rapamycin is actually slowing the aging process and improving the health span of mammals.
Experimenting is needed in the space, and tying in other theories and ideas is crucial to making advancements.
Let’s Connect!
If you found this interesting and want to learn more, connect and let’s talk!
Check out the video I made on this project too!
