Life Extension Benefits of Rapamycin
Do you want to live longer healthier? Is so, then rapmycin is something you will want to know. Rapamycin is the hot topic in the life extension or longevity arena. Rapamycin has been shown to increases median life expectancy up to 60% in animal models. That is impressive and human studies have been and are being conducted currently with encouraging preliminary results.
It is one thing to extend life span but it is quite another to extend health span – the additional years lived in good health. Let’s face it, few of us want to live longer in a poor state of health. That’s the other promising feature of rapamycin. At least, in animal models rapamycin seems to reduce the prevalence of chronic disease like diabetes, obesity, and cancer, thus improving health span as well – the ability to live longer in a good state of health.
Why Live Longer?
Before we go too far, why should be people want to seek out life extension therapies? Well, if you love your life, and what you do, and are positively impacting those around you, and society in general, would you not want the opportunity to keep having that effect for a longer period of time? Life extension is a way to leverage your impact on the world. Now, if your life sucks (I hate to use that word), then life extension makes little sense.
Also, don’t you want to stay physically healthy longer to do more traveling and obtain as many life experiences as possible? Life extension gives you an opportunity to get the most from life and to give the most back to it.
Life extension is for the achievers, the doers, those that make things happen. Are you one of them? If so, then read on.
In our article, 12 Powerful Hallmarks of Aging we discussed the known mechanisms of aging. A healthy lifestyle works across all those hallmarks of aging, but we are now at a point where can target some of these specific hallmarks of aging with nutritional supplements and through the careful application and repurposing of existing medications that are alreadg FDA approved.
Rapamycin is one of those existing medications. Metformin is another such medication which we will discuss briefly in this post. But, today we will focus primarily on rapamycin.
What is Rapamycin?
What is rapamycin? Rapamycin is a compound produced by the bacterium Streptomycin hygroscopic. Rapamycin was discovered in 1972 in soil samples found on Easter Island. Its name comes from the native name of the island which is Rapa Nui. Rapamycin is also known as sirolimus and its brand name is Rapamune.
It is an FDA approved drug since 1999 and most often used as immunosuppressant in patients with kidney transplants. Isn’t suppressing the immune system potentially bad? It can be. In the case of organ transplants a certain level of immune system suppression is a desirable to prevent rejection of the transplanted organ.
When prescribed in patients with organ transplants rapamycin is prescribed on an ongoing basis. But periodic pulses of rapamycin has life extension benefits while reducing and avoiding the immunosuppressant effects. That is a key difference when using rapamycing for longevity purposes. You do not take it daily.
How Does Rapamycin Work?
Understanding how rapamycin works for life extension is critical to those who may want to take the medication. In addition, to its immunosuppression effects, rapamycin also has anti proliferative effects which means it can stop cells from overgrowing in including some cancer cell-types.
How does it do this?
Rapamycin inhibits the mechanistic target of rapamycin, also called mTOR for short. mTOR is a protein kinase encoded by the mTOR gene and plays a role in insulin, growth factor, and amino acid pathways.
mTOR and Autophagy
A key to healthy aging is having a healthy or balanced interplay between mTOR and autophagy. Imbalance or dysregulation of mTOR and autophagy leads to chronic disease like obesity, diabetes, cancers, dementia, autoimmune disease, and lymphoproliferative diseases, and a shortened life span in animals.
What is autophagy? Autophagy is a process where damage proteins, excess fat, and other worn cellular components are broken down and either reused or eliminated from the body. You can think of autophagy as taking out the garbage while recycling some of it. Autophagy restores youthful metabolic functions.
Here is how rapamycin affects mTOR.
When calories are present, the protein mTOR sends signals to cells to activate cellular metabolism telling the cell that is has calories, nutrients, and oxygen to build new proteins, new enzymes, fat stores, etc. mTOR is a sensing protein.
When mTOR is activated it initiates anabolic (tissue building) processes of cell growth and proliferation, but unchecked cell growth and proliferation is not desirable. Unchecked growth and proliferation leads to obesity, cancer, and diabetes.
Rapamycin inhibits mTOR thus halting or reducing cell growth and proliferation. By inhibiting mTOR, rapamycin allows autophagy to occur.
We have what are known as Zombie cells. These are cells that are nonfunctional but metabolically active which triggers inflammation and other unwanted biochemical processes. These cells are senescent – old and worn out and they take up space from healthy cells. They do not improve health, and in fact, are detrimental to good health. Autophagy is the process to remove these senescent or Zombie cells.
Nutritional supplements and medications that clear out senescent cells are known as senolytics and we will write a dedicate article on senolytics.
When mTOR is activated, autophagy cannot occur. Our constant access to food 24/7/365 creates a problem. For probably close to 99% of mankind’s existence humans did not eat as frequently as we do today. Constant eating activates mTOR. This prevents autophagy. It has been known for years the calorie restriction improves longevity in fruit flies, yeast, worm, and mammals. This has to do with the fact that with calorie restriction mTOR is not constantly activated and autophagy can occur.
Autophagy is activated when we are in a fasting state. You can probably now see why there are health benefits to time-restricted eating and fasting.
By inhibiting mTOR, rapamycin provides the benefits of being in a fasted state, and possibly better than actual fasting.
What is the proper balance between mTOR activation and autophagy? We really don’t know, but some experts like Ross Pelton, a pharmacist, who has studied mTOR and autophagy thinks that mTOR should only be activated 15% of the time and autophagy activated 85% of the time.
If you are like most people and eating over a period of 14 hours a day, then mTOR is potentially activated 58% of the time and autophagy only 42% of time. If that goes on day after day, month after month, year after year, then the chances of you developing a chronic disease and having a shortened life span go up.
AMPK and Activation of Autophagy
There is another molecule or compound you need to understand and that is the enzyme AMPK. AMPK is short for Adenosine 5′ monophosphate-activated protein kinase. It is the enzyme that activates autophagy. The good news is that there are natural activators of AMPK including intermittent fasting, calorie restriction, exercise, green tea, curcumin, piperlongumine (a spice), luteolin, and the diabetes medication called metformin.
Metformin is now being studied as an anti-aging drug. Metformin is readily available and is very inexpensive and has been used in humans for diabetes in Europe since the 1957 but did not received FDA approval in the United States until 1995. Metformin is an AMPK activator and also an mTOR inhibitor
The Bannister Study showed that diabetics taking metformin lived the same number of years as people without diabetes which is remarkable given that diabetics on other medications die 10 years sooner than non-diabetics.
Not only that, but diabetic individuals over 70 taking metformin lived longer than their age-matched non-diabetic peers.
Again, metformin activates AMPK which then triggers autophagy restoring metabolic processes to a youthful level. It also has anti-inflammatory and anti-cancer effects, at least in diabetics.
Rapamycin Dose for Life Extension
In 2010 a study on humans was completed using rapamycin. Two-hundred eighteen individuals over age 65 were study participants. They were divided into a placebo group and three treatment groups. Group 1 received 0.5 mg rapamycin daily for 6 weeks. Group 2 individuals received 5 mg of rapamycin weekly for 6 weeks. Participants in group 3 received 20 mg of rapamycin weekly for 6 weeks.
After a 2 week wash-out period these participants were given the flu shot. The participants in the 5 mg weekly dose saw an enhancement of 20% to their immune system response to the flu vaccine. The other treatment groups did not. So 5 mg weekly was the sweet spot in that study.Thus, the moderate dose weekly did not suppress their immune system and actually improved it.
Based on this study most physicians who prescribe rapamycin for life extension use 5 mg to 6 mg of rapamycin on a weekly basis. Typically, blood counts are followed specifically white blood cell counts (immune function). If a drop in white blood cell count is seen then physicians will typically dose the rapamycin every 10 to 14 days or use a lower dose as to not suppress immune function.
Animal Studies on Rapamycin
When rapamycin was administered to middle-aged mice median life expectancy increased 60%. When rapamycin was administered to elderly mice (roughly equivalent to 60 year-old men and women), there was a 14% increase in life expectancy among the female mice and 9% increase in male mice which may translate to an increase of 7 or more human years.
Thus, it would seem reasonable for humans to start rapamycin for life extension during middle-age to obtain the most benefit.
Since childhood, adolescence, and young adulthood are characterized by growth when growth is essential, it would be inappropriate and unwise to use a mTOR inhibitor like rapamcyin in those age groups.
While there is no agreed upon age for initiating rapamycin, starting sometime after age 30 seems reasonable pending outcomes of future human studies. Based on mice studies, rapamycin probably provides less benefit above the age of 60 but nonetheless can be safely prescribed and may add 7 years of life on average. More benefit can be expected if taking rapamycin at an early-middle age range.
Rapamycin is reasonably affordable but since it is used off-label for life extension it is not likely to be covered by health insurance. The price for 50 one mg tablets of Rapamycin can be obtained for around $70. If taking 5 mg weekly, that is $70 for a 10 week supply. The bigger challenge is finding a physician who understands the science behind rapamycin, mTOR, autophagy, and AMPK activation, and is willing to prescribe rapamycin to a well-informed patient.
We will write a more in-depth article on the longevity benefits of metformin in the near future.