The Science of Rapamycin & mTOR:
Understanding its Mechanisms and Effects on Aging. [Part 4] Outlive By Peter Attia
Announcement:
I’m getting married this weekend, ideally, I should be sleeping during the time I would normally post, so I thought it would be better if write it earlier and release it! I am very serious about my consistency and will try to maintain it unless it is impossible for me to write a post.
Introduction
Rapamycin, also known as Sirolimus, is a bacterial product discovered in 1972.
It was initially used as an anti-fungal agent before researchers discovered its immunosuppressive properties.
The drug was approved by the FDA in 1999 for use in preventing organ transplant rejection.
When someone receives an organ transplant, their body recognizes the organ as foreign and activates the immune system to attack it.
This is because the immune system cannot distinguish between the person's cells and those of the donor.
To prevent rejection, patients must take immunosuppressive drugs like rapamycin that suppress the immune response and prevent the body from attacking the transplanted organ.
However, long-term use of immunosuppressive drugs can increase the risk of infections and other complications. We’ll talk about this later.
Its other applications were:
Rapamycin is also used as a coating on arterial stents because it prevents the stented blood vessels from reoccluding.
In 2007, a rapamycin analog called everolimus was approved for use against a type of kidney cancer.
An analog is a compound that is similar in structure and function to another compound.
The initial discoverer of this molecule, Sehgal observed that it tends to slow down the process of cell growth and division.
Later studies showed that it also had potential anti-aging properties, by inhibiting the activity of the protein complex mTOR.
A protein complex refers to a group of two or more proteins that bind together to execute a specific biological function.
This has made it a subject of much research, with scientists investigating the mechanisms that make rapamycin effective and potential ways to use it to promote healthy aging.
Why do we care about mTOR?
Because it turns out to be one of the most important mediators of longevity at the cellular level.
The job of mTOR is basically to balance an organism’s need to grow and reproduce against the availability of nutrients.
When food is plentiful, mTOR is activated and the cell (or the organism) goes into growth mode, producing new proteins and undergoing cell division, with the ultimate goal of reproduction.
When nutrients are scarce, mTOR is suppressed and cells go into a kind of “recycling” mode, breaking down cellular components and generally cleaning house.
Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy.
Not only that, but it is highly “conserved,” meaning it is found in virtually all forms of life, ranging from yeast to flies to worms and right on up to us humans.
In biology, “conserved” means that something has been passed on via natural selection, across multiple species and classes of organisms—a sign that evolution has deemed it to be very important.
A study was conducted using rapamycin on mice, which showed that the drug could extend lifespan by postponing death from cancer or retarding mechanisms of aging.
The drug had boosted the animals' remaining life expectancy by 28% for males and 38% for females, with results consistent across multiple experiments and labs.
Three different labs and across 1901 genetically diverse animals.
These findings are significant as no other molecule had ever been shown to extend lifespan in a mammal before.
There were many other molecules resveratrol and nicotinamide riboside(NR) which initially showed promise but didn’t show consistent results when tried to reproduce.
So rapamycin producing consistent results is a big deal!
It has also been shown to do so in yeast and fruit flies, sometimes alongside genetic manipulations that reduced mTOR activity.
Thus, there is something good about turning down mTOR, at least temporarily—and rapamycin may have the potential as a longevity-enhancing drug.
Caloric Restriction and its Effects on mTOR
Caloric restriction without malnutrition (CR) has been shown to increase the lifespan of mice and rats by 15-45% and improve their healthspan.
CR is an experimental method where animals are given a similar diet with all necessary nutrients but with 25-30% fewer total calories compared to the control group who can eat as much as they want
Furthermore, underfed animals develop fewer tumors than their normally fed counterparts, and CR seems to improve their healthspan.
Healthspan refers to the period of an individual's life where they are free from chronic diseases and maintain overall physical and mental well-being.
It has been shown to improve lifespan not only in rats and mice (usually) but also in yeast, worms, flies, fish, hamsters, dogs, and even, weirdly, spiders.
It has been found to extend lifespan in just about every model organism on which it has been tried.
It is important to note that the effects of CR are dose-dependent, similar to a drug.
This means that the effects of caloric restriction on longevity and healthspan are not a linear relationship.
Rather, there is a specific threshold of caloric restriction that leads to the most benefits, and beyond that point, further restriction may become detrimental.
This is similar to how the effects of a drug depend on the dose - a lower dose may have no effect, a moderate dose may be beneficial, and a high dose may have harmful side effects.
The usefulness of caloric restriction for increasing lifespan remains uncertain outside of lab settings.
Severe caloric restriction may be difficult to sustain for humans and could lead to increased mortality from infections, trauma, and frailty.
It is unclear whether extreme CR would truly maximize longevity in complex organisms like humans living in more variable environments.
The real value of caloric restriction research lies in the insights it has contributed to our understanding of the aging process itself.
CR studies have helped to uncover critical cellular mechanisms related to nutrients and longevity.
Reducing the amount of nutrients available to a cell seems to trigger a group of innate pathways that enhance the cell’s stress resistance and metabolic efficiency—all of them related, in some way, to mTOR.
The first of these is an enzyme called AMP-activated protein kinase, or AMPK for short.
When it senses low levels of nutrients, it activates, triggering a cascade of actions.
It first starts with the production of new mitochondria through a process called mitochondrial biogenesis.
Our mitochondria become vulnerable to oxidative stress and genomic damage, leading to dysfunction and failure.
By replacing the old, damaged ones with newer, more efficient ones helps cells produce more energy with less fuel.
AMPK also prompts the body to provide more fuel for these new mitochondria, by producing glucose in the liver and releasing energy stored in fat cells.
It also inhibits the activity of mTOR.
By doing so, it prompts the cell to activate an important cellular recycling process called autophagy.
Autophagy: Why does it matter?
Autophagy: The process of breaking down old proteins and other cellular structures into their amino acid components and repurposing them.
Autophagy is essential to life. If it shuts down completely, the organism dies.
Imagine if you stopped taking out the garbage (or the recycling); your house would soon become uninhabitable.
Except instead of trash bags, this cellular cleanup is carried out by specialized organelles called lysosomes, which package up the old proteins and other detritus, including pathogens, and grind them down (via enzymes) for reuse.
In addition, the lysosomes also break up and destroy things called aggregates, which are clumps of damaged proteins that accumulate over time.
Protein aggregates have been implicated in diseases such as Parkinson’s and Alzheimer’s disease,
By cleansing our cells of damaged proteins and other cellular junk, autophagy allows cells to run more cleanly and efficiently and helps make them more resistant to stress. But as we get older, autophagy declines.
This very important cellular mechanism can be triggered by certain kinds of interventions, such as a temporary reduction in nutrients (as when we are exercising or fasting)—and the drug rapamycin.
Other benefits of Rapamycin
A study found that the rapamycin analog everolimus enhanced the adaptive immune response to a vaccine in older patients.
Patients on a moderate weekly dose of everolimus had the best response to the flu vaccine with the fewest side effects.
This suggests that rapamycin and its derivatives might be more of an immune modulator than an immunosuppressor, as previously believed, with some dosing regimens enhancing immunity and others inhibiting it.
It appeared that the immune suppression resulted from the daily use of rapamycin at low to moderate doses.
The study subjects had been given moderate to high doses followed by a rest period, and this cyclical administration had had an opposite, immune-enhancing effect.
It seems odd that giving different doses of the same drug could have such disparate effects, but it makes sense if you understand the structure of mTOR, which is actually composed of two separate complexes, called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
The two complexes have different jobs, but (at risk of oversimplifying) the longevity-related benefits seem to result from inhibiting complex 1.
Giving the drug daily, as is typically done with transplant patients, appears to inhibit both complexes, while dosing the drug briefly or cyclically inhibits mainly mTORC1, unlocking its longevity-related benefits, with fewer unwanted side effects.
Rapamycin has potential geroprotective(delaying aging) effects, but its side effects remain a hurdle for clinical trials in humans.
A large clinical trial on companion dogs is being conducted to address these concerns.
Preliminary results have shown that rapamycin improves cardiac function and reduces systemic inflammation, possibly by reducing the activity of senescent cells.
It also improves cancer surveillance, the ways in which our body, most likely the immune system, detects and eliminates cancer cells.
It not only seems to delay the decline but also has a rejuvenating function in some organs.
Treating Aging as a Disease
The real obstacle here is a regulatory framework rooted in Medicine 2.0, which does not (yet) recognize “slowing aging” and “delaying disease” as fully legitimate endpoints.
This would represent a Medicine 3.0 use for this drug, where we would be using a drug to help healthy people stay healthy, rather than to cure or relieve a specific ailment.
Thus, it would face much more scrutiny and skepticism. But if we’re talking about preventing the diseases of aging, which kill 80 percent of us, then it’s certainly worth having a serious conversation about what level of risk is and isn’t acceptable in order to achieve that goal.
Metformin and Beyond
The FDA has given the green light for a clinical trial of another drug with potential longevity benefits, the diabetes medication metformin.
This trial is called TAME (Targeting Aging with Metformin).
Metformin has been taken by millions of people for years.
Patients on metformin appeared to have a lower incidence of cancer than the general population.
One large 2014 analysis seemed to show that diabetics on metformin actually lived longer than nondiabetics, which is striking.
But none of these observations “prove” that metformin is geroprotective—hence the need for a clinical trial.
But aging itself is difficult—if not impossible—to measure with any accuracy. Instead, TAME lead investigator Nir Barzilai decided to look at a different endpoint: whether giving metformin to healthy subjects delays the onset of aging-related diseases, as a proxy for its effect on aging.
Peter is hopeful that someday, maybe in the near future, we could attempt a similar human trial of rapamycin, which he believes has even greater potential as a longevity-promoting agent.
Conclusion
In conclusion, we looked at the potential of drugs like rapamycin and metformin to promote longevity and delay the onset of aging-related diseases. While there are still hurdles to overcome, such as the regulatory framework and side effects of these drugs, the TAME trial and other studies provide promising evidence.
We need to shift from Medicine 2.0 to Medicine 3.0, where the focus is on keeping healthy individuals healthy, rather than just treating specific ailments.