In 1972, a compound was identified from a bacterial species (Streptomyces hygroscopicus) originally found off the coast of Chile on Easter Island. The compound was developed to prevent fungal infections but later was found to do other things, like suppress the immune system. In fact, a primary use for it currently is to prevent organ rejection in transplant patients. Due to other interesting effects, however, the predominant use of this compound may change in the not-too-distant future. It’s possible this compound can help us age better. The compound is called rapamycin.
Rapamycin acts through the suppression of a biochemical pathway after which it is named – the “mechanistic target of rapamycin,” or mTOR for short. Let’s first discuss the mTOR pathway and why it’s important for aging, and then we’ll take a closer look at the anti-aging properties observed with rapamycin. We’ll also discuss whether this is something you can benefit from now.
(This is the sixth blog in my series of articles on better aging. You can find the rest of them here: 1, 2, 3, 4, 5.)
mTOR
Like other pathways of interest for better aging, mTOR evolved as a way for organisms to survive during periods where the supply of food was unstable. mTOR itself is an enzyme found in the cytosol of cells. It responds to a wide range of signals, including oxygen, amino acids, energy levels, hormones, and growth factors. Once stimulated, it regulates a huge host of processes including protein and lipid synthesis, energy metabolism, cell structure, and cell survival. It is the influence of the mTOR enzyme on all these processes that is considered the “mTOR pathway.”
Generally, mTOR activation directs metabolic processes toward growth. For example, activating a version of the mTOR enzyme (mTORC1) encourages feeding, energy storage, and the formation of new insulin producing β-cells in the pancreas (all processes that favor growth). See the footnote at the bottom for additional mTOR biochemistry.
What does all of this have to do with aging? Many processes that lead to better longevity outcomes, like calorie restriction, fasting, and protein restriction, stimulate autophagy – a process within cells that cleans up broken proteins, bacteria, and viruses. Activating mTOR, however, prevents autophagy from occurring. Therefore, suppressing mTOR – why rapamycin does – may have longevity benefits. It is this effect, plus others like its suppression of cell division and growth, that immediately raised interest for its study in the field of aging sciences. But herein lies a cautionary tale for all potential aging therapeutics. Remember, mTOR affects many processes important for biological functioning. We must proceed with caution and resist the mentality that if some is good, more is better. Read on to hear why in this specific case.
Using rapamycin to inhibit mTOR and extend lifespan
In 2009, David Harrison of Jackson Laboratory in Bar Harbor Maine and colleagues showed that giving rapamycin to mice makes them live longer. The researchers first aged mice to the equivalent of a 60-year-old human, in terms of lifespan. They then gave them rapamycin with their food, while the same-aged control mice were given the same diet without the drug. Compared to controls, rapamycin increased lifespan by nearly 10% for males and 15% for females.
You might suspect there to be even more profound survival benefits if they were to start the mice on rapamycin earlier in life. This hypothesis was tested in a subsequent study in 2011. Perhaps surprisingly, starting rapamycin earlier did not make them live any longer than had been previously seen. This is encouraging because people most eager to stave off aging tend to be older people experiencing some of its ill effects. As one ages, he or she typically becomes more motivated to address aging directly, which means that if these results were to translate to humans, we would need to start taking the drug at about the time we were more motivated to do so. Indeed, it’s hard to get 20-to-30-year-olds to shape lifestyle to emphasize better aging outcomes
Before you try to procure some, rapamycin treatment comes with some serious tradeoffs. In fact, observed metabolic side effects make it unclear whether the drug is safe as a long-term treatment. Studies on rodents and humans found deterioration of the metabolic profile, with insulin resistance and hyperlipidemia. Over the long term, these problematic side effects could be expected to shorten, rather than prolong, lifespan. As you will see, the dosing regimen could make all the difference as to whether this is a compound that helps or hurts those interested to age better.
Trials in primates
The common marmoset provides a good non-human primate model for human aging and chronic disease due to it size and shorter lifespan, and due to a metabolism that is relatively comparable to humans. A recent study by Corinna Ross at Texas A&M and colleagues, published in the journal Aging, looked at the long-term treatment with encapsulated rapamycin in these monkeys.
“From 2010-2011, we conducted a year-long study of daily dosing of a group of common marmosets with rapamycin. We previously reported that we were able to maintain circulating blood levels of rapamycin at 5.2 ng/mL by giving the animals a dose of eudragit encapsulated rapamycin in yogurt of 1mg/kg/day. Subjects demonstrated a decrease in mTORC1 after two weeks of treatment. We found that long-term treatment resulted in no overall effects on body weight and only a small decrease in fat mass over the first few months of treatment.”
Because the Ross study was so positive, the Barshop Institute, where the research took place, was awarded a $2.7 million grant from the National Institute on Aging to support the next step, which is to give middle-aged marmosets rapamycin for a longer period of time to assess the impact on lifespan and markers of chronic disease.
A possible explanation for the metabolic differences might be in the mode of administration. In the studies that showed a lifespan-extending effect, the researchers added microencapsulated rapamycin to the diet, rather than injecting it into the intraperitoneal cavity. The former method would be expected to result in lower bioavailability of the drug. So, like with most substances we put into our body, the dose makes the poison. It’s clear the amount of rapamycin (or the amount that is absorbed in the body) needs to be optimized to achieve both longevity and cardio-metabolic health.
Is rapamycin something humans can benefit from right now?
When you hear about a substance extending lifespan by 10-15% in mice, and then it shows a favorable safety profile in a solid primate model for human aging, it piques curiosity. I would be especially curious if I were currently a 65-year-old wanting to live to 90 instead of 80. Its promise is seductive, but I would hold off, personally, and here are a few reasons why. First,
we need further assessment to determine safety, health markers, and quality of life, in relatively healthy humans. If everything looks okay, the compound is tolerated and safe, then longer-term trials can gauge a potential longevity boost in humans. Remember, the mTOR pathway affects many processes to keep our cells functioning. Suppressing it too intensely is clearly not good; we need a lighter touch. Not only do we need to establish the right dose for us, but we also need to identify the right treatment regimen. From the Ross study above, it took about two weeks to demonstrate significant suppression of mTOR1C. Sensible usage strategies (if there are any) for rapamycin could, for example, be for those aged 60 years and older to either use a low daily dose or to use it for 30 days at a time every 6 months or so. We’ll see. In the meantime, rapamycin is not the only way to suppress the activity of mTOR. You can also do this with occasional-to-regular protein restriction and fasting, which are lifestyle behaviors that have aging benefits beyond mTOR suppression, and are activities you can elect to partake in now.
Footnote: additional biochemistry
The mTOR pathway is initiated when growth factors and some nutrients bind to receptor tyrosine kinases on the surface of cells. This results from the signaling of PI3K / AKT pathway and the activation of mTOR. Subsequently, mTOR phosphorylates the transcription factor 4EBP1 and the kinase S6K1 which regulate the translation of proteins involved in cell growth and proliferation. This pathway is regulated by the TSC1/2 complex which inhibits mTOR activity and helps control the growth and proliferation of cells. Overactive mTOR signaling leads to uncontrolled cell growth and proliferation.
References
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274-293.
