Rapamycin, mTOR, and Your Genes

Key takeaways:
~ Rapamycin is an antibiotic traditionally used as an immunosuppressant and an anti-cancer agent.
~mTOR is responsible for sensing the fasting state (low nutrients) and the fed state (plenty of nutrients).
~ Through inhibiting mTor, rapamycin is now the focus of longevity and healthspan-extending research.
~In addition to rapamycin, lifestyle changes can inhibit mTor.

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Rapamycin, mTOR, and healthspan:

Discovery of Rapamycin:  Rapamycin was discovered in soil on Easter Island in 1975.[ref] The name comes from Rapa Nui, the native name for Easter Island, an island in the South Pacific. Researchers isolated a bacteria (Streptomyces hygroscopicus) in the soil, and from that bacteria, they found a compound they named rapamycin. Because it inhibits Candida, rapamycin was initially developed as an antifungal. But the researchers found that it also suppressed the immune system, which at the time was considered a big drawback to using rapamycin as a drug.

Fast forward a decade and organ transplants were becoming more common. Researchers came back to rapamycin, using it as an immunosuppressant to be given after organ transplants to prevent rejection. It is still an FDA-approved drug used for transplant patients.

Rapamycin and mTOR:

Researchers figured out a decade or more ago that rapamycin expands lifespan in lab animals including mammals by around 15-25%.[ref][ref] This kicked off a lot of research on rapamycin and longevity.

There was a lot of interest in figuring out how the molecule works. Specifically, researchers wanted to find out what rapamycin is acting on in the body that causes an increase in lifespan. Which ‘switch’ did it throw to cause a 25% life extension?

This led to the discovery of mTOR, which is one of the central regulators of growth in the body. Dr. David Sabatini has recently been awarded the 2020 Sjöberg Prize for “discovering the mTOR protein and its role in controlling cell metabolism and growth.”[article] (video below)

What is mTOR?

mTOR stands for mammalian (or mechanistic) Target Of Rapamycin.

mTOR is responsible for sensing the fasting state (low nutrients) and the fed state (plenty of nutrients). Rapamycin acts as an inhibitor of mTOR to make the changes that caused the extension of lifespan.

To get a bit more technical, mTOR is sensing nutrients (glucose, amino acids, oxygen, growth factors) and switching the body between anabolism and catabolism:[ref]

• Anabolism is the building up of new cells and tissues (I always think about ‘anabolic steroids’ and bodybuilders to remember what anabolism means)
• Catabolism is the breaking down of tissue and cells and recycling the proteins (autophagy)

When mTOR is activated by sensing abundant nutrients, it activates a bunch of different anabolic – or growth-related – pathways.

mTOR forms complexes with a couple of other proteins.

• mTORC1 (mTOR complex 1) includes mTOR and the proteins called RPTOR, mLST8, PRAS40, and DEPTOR. This protein complex activates the translation of other proteins when a cell needs to manufacture more proteins for growth. mTORC1 is what rapamycin acts on and inhibits.
• mTORC2 contains mTOR along with the proteins mLST8, Rictor, mSIN1, and Protor1/2. Rapamycin doesn’t inhibit mTORC2 as well, at least not initially.[ref] Thus, research is now focusing on other molecules that are similar to rapamycin, but better at also inhibiting mTORC2. These rapamycin analogs are known as rapalogs.[ref]

As you can imagine, activation of mTOR is great for promoting growth when a person is young. But there are tradeoffs between wanting growth in youth and no longer wanting growth in adults and in aging. There has to be a balance between breaking down old cells and building up new cells – with a check or inhibition of uncontrolled cell growth (e.g. tumors).

Rapamycin as an anti-aging compound:

If you want to extend the lifespan of a lab animal, calorie restriction is one surefire way to do so. But it doesn’t work as well in long-lived animals or in humans. Calorie restriction – or lack of nutrients – inhibits mTOR.

Rapamycin, as a way of inhibiting mTOR, mimics the effects of calorie restriction.

Many animal studies show that rapamycin, through inhibiting mTOR, can extend lifespan and repress some of the decline in function due to aging.[ref][ref]

Research also points to rapamycin being beneficial as an anti-aging compound by possibly inhibiting cancer (people generally live longer when they don’t die of cancer).[ref]

Extending healthspan and lifespan in dogs:

Everyone is saddened to see a family pet decline with age, and the idea of preventing age-related decline in a beloved pet is tantalizing. Several clinical trials show promise for extending health span and lifespan in dogs using rapamycin.[ref]

One of the really interesting trials is the ongoing Dog Aging Project. The researchers are partnering with pet owners in a large-scale trial of rapamycin in pet dogs. The project seeks to determine how real-world lifestyle factors (environment, food, and activity) interact with rapamycin in slowing aging in dogs.

Extending healthspan in humans?

Does Rapamycin work to extend lifespan in humans? We don’t have solid data yet from any trials showing that rapamycin extends lifespan. Obviously, those types of trials take a lot of money and a long time to conduct.

Instead, the more important question – at least to me – is “can rapamycin extend healthspan?”

In the normal course of aging, the last years of life are often spent in ill health with pain, problems with mobility, and a big decrease in the quality of life.

Healthspan covers the part of your life that you spend as a (relatively) healthy person, and extending healthspan is an important goal in anti-aging / longevity research.

Inhibiting mTOR is one pathway that anti-aging research focuses on.

There are several ways that inhibiting mTOR may increase healthspan:

• improving immunosenescence
• increasing autophagy
• blocking atherosclerosis
• improving cognitive function in aging

Improving immunosenescence with rapamycin:

Immunosenescence is the “decline in immune function that occurs during aging”.

This decline in immune function directly leads to increased infections, including increased respiratory tract infections which are a leading cause of death in elderly people (to be specific – the 4th leading cause in people >85, 8th leading cause in people >65).[ref]

Let me back up a minute and explain what senescence means…
Cellular senescence occurs when a cell has reached the end of its lifespan and can no longer divide or when there is DNA damage that can’t be repaired. At this stage, the cell gives off inflammatory signals that prompt the immune system to come in and kill off the cell, recycling the proteins to be used elsewhere. This is one way the body stops the proliferation of cells that could be cancerous.[ref]

Cellular senescence occurs throughout life, but with aging, there is an accumulation of senescent cells that aren’t cleared out quickly enough.

When these senescent cells build up in the body, the inflammatory cytokine signals that are released damage the surrounding cells as well.

Circling back to immunosenescence – this term applies when immune system cells become senescent, which causes the immune system not to function as well. Specifically, the innate immune system is likely to be impaired with a decreased interferon response. This means that the first line of defense against viral and bacterial pathogens is not as robust. Additionally, the adaptive immune system has a decreased ability to respond to new pathogens (or vaccines). Finally, there is a lingering low-level inflammation due in part to the senescent immune cells.

How can rapamycin help with immunosenescence?
A recent clinical trial used a rapalog (mTOR inhibitor) drug that is in development. The trial, conducted in elderly subjects, looked at the immune response by investigating antiviral gene expression, response to the flu vaccine, and the number of infections reported during the year following the 6-week trial. The results showed that the rapalog was safe and significantly decreased the rate of infections in the elderly participants as well as upregulating antiviral gene expression.[ref] Note that this clinical trial used a low-dose rapamycin analog (rapalog) and not rapamycin. 

Rapamycin and autophagy:

As an inhibitor of mTOR, it makes sense that rapamycin would increase autophagy, which is the clearing out and recycling of cellular waste. Indeed, studies show that rapamycin increases autophagy.

A 2019 study shows that rapamycin induces both macroautophagy and microautophagy.[ref] This means that rapamycin is able to increase the recycling of damaged organelles (such as mitochondria) as well as nutrient recycling when fasting.

Studies show that autophagy is decreased in aging for most people. This has been shown in brain aging, osteoarthritis, and even in immunosenescence studies.[ref] Increasing autophagy is one strategy to combat the diseases of aging.

Atherosclerosis:

Cardiovascular disease is the number one cause of death in the elderly. Atherosclerosis is the buildup of plaque in the arteries, which narrows the arteries leading to hypertension and an increased risk of a heart attack.

Cellular senescence in the cells lining the blood vessels plays a role in atherosclerosis. The senescent cells give off inflammatory cytokines, causing inflammation and the build-up of plaque in the blood vessel walls.

Cell studies show that rapamycin can block or reverse that cellular senescence. It seems to do this through upregulating autophagy.[ref]

Animal studies show that even with high levels of cholesterol, rapamycin can block the inflammation and formation of atherosclerotic plaque.[ref]

Other studies show that rapamycin can block NF-kB, an inflammatory cytokine, and decrease the oxidation of LDL cholesterol.[ref] Oxidized LDL cholesterol is a major risk factor in atherosclerosis.

Animal studies also show that elderly animals benefit from rapamycin for heart health.[ref]

Rapamycin and the aging brain:

Mouse models of Alzheimer’s disease have been used to show that rapamycin may be effective in treating neurodegeneration through a couple of mechanisms including targeting tau pathology and improving blood-brain barrier function.[ref][ref][ref]

Let me be clear: while mTOR inhibition is an interesting avenue that researchers are pursuing, there are no human clinical trials yet showing that rapamycin would be beneficial for Alzheimer’s disease.

Some researchers theorize that rapamycin or an mTOR inhibitor given when dementia is present may be harmful rather than beneficial. They point out that mouse trials use rapamycin earlier in life before the pathology of Alzheimer’s has progressed.[ref] Indeed, rapamycin given to mice after cognitive decline started did not reverse the cognitive decline.[ref]

Preventing jaw bone loss with rapamycin:

A study published in April 2020 shows exciting results in an animal model of aging dental health. One perhaps under-appreciated aspect of the decline in health with aging is that a loss of teeth can greatly impact nutrition status. Additionally, oral infections can cause systemic inflammation. Plus there are all kinds of links between gum disease and heart disease…

The new study (in mice) found that “short-term treatment with rapamycin rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition.”

Researchers noted three important changes due to rapamycin:[ref]

• The inhibition of RANKL, a protein important in bone breakdown and bone growth, which decreased the breakdown of the jaw bone
• Suppression of NF-kB, an inflammatory cytokine
• Restoration of the oral microbiome to that of a young animal

The latest study adds to the results of previous animal studies on rapamycin and oral health.[ref]

Rapamycin in cancer treatment therapy:

Numerous trials have looked at rapamycin as a treatment for cancer. Some have shown promising results, such as for refractory Hodgkin lymphoma[ref], but not all trials show positive results.

One interesting patient report showed a rapamycin derivative, everolimus was very effective in a person with mTOR activating genetic variants. This points to a need for personalization in cancer treatment.

Combining rapamycin with metformin for anti-aging:

At the top of the list of anti-aging drug possibilities is the combo of rapamycin and the diabetes drug metformin. Both drugs inhibit mTOR, to some extent, and both are beneficial for cardiovascular disease and anti-aging. Metformin works as a diabetes drug by increasing insulin sensitivity and decreasing the production of glucose in the liver.[ref]

So why aren’t doctors writing everyone over a certain age a prescription for metformin and rapamycin? Well, side effects – along with questions about long-term safety and effectiveness. There are currently anti-aging trials underway to see whether the benefits are worthwhile for the population as a whole. (And hopefully, there will be trials to determine which people genetically are more likely to benefit from rapamycin.)

A small, short-term safety trial in adults aged 70-95 showed that side effects were minimal but that there were also no great effects in terms of physical performance, cognitive enhancement, or immune function.[ref]

Rapamycin has links to the possibility of increasing blood glucose levels (which metformin counteracts).[ref] The timing and duration of dosing with rapamycin make a difference when it comes to glucose intolerance, and more long-term human trials are needed before giving out rapamycin to everyone as an anti-aging drug.[ref]

Metformin is linked with gastrointestinal side effects in people with certain genetic variants: my whole article on metformin and genetics.

Side effects of Rapamycin:

Rapamycin is a prescription medication authorized for use in people who have health conditions (organ transplants, cancer). Studies do show some adverse events in people with renal transplants that may be due to rapamycin. These complications include altered wound healing, diarrhea, pneumonia risk, and altered electrolytes.[ref]

Rapamycin suppresses the immune system, which can be a very serious side effect in certain situations. Additionally, rapamycin can cause glucose intolerance, raising blood glucose levels in some people.[ref]

Rapamycin is a prescription medication in most places in the world, so talk with your doctor to learn more about the side effects and possible counterindications that are personal for your situation.

Similar drugs to rapamycin:

Everolimus, a drug marketed by Novartis (Certican, Afinitor), is a derivative of rapamycin. It is prescribed as an immunosuppressant and for kidney cancer.

Everolimus is metabolized by CYP3A4 and CYP3A5. It has greater oral bioavailability than rapamycin.[ref]

Topical rapamycin/sirolimus:

A clinical trial shows that a topical cream containing 0.2% sirolimus (rapamycin) inhibits mTOR in the skin, which improves skin lesions in people with tuberous sclerosis complex (a genetic disease that activates mTOR).[ref]

Lifehacks:

Rapamycin is a prescription medication in the US. Some doctors may be willing to prescribe it off-label for anti-aging purposes if appropriate for your situation. I’m not going to go into the ways of ordering rapamycin without a prescription – you can google that for yourself.

mTOR and depression – a word of caution:

While inhibiting mTORC1 may be beneficial for healthspan and longevity, this may not be the right move for someone dealing with depression. Stimulating mTOR has been shown to be beneficial for depression, and people with major depressive disorder have been shown to have deficits in mTOR in the brain.[ref][ref] Several drugs being researched for depression, including ketamine, act on mTOR.[ref][ref]

If you are dealing with depression or are on an antidepressant, be aware that even natural ways of inhibiting mTOR may impact your mood disorder.

Natural ways to inhibit mTOR:

Simply put, mTOR increases when fed and decreases when fasted. Thus, fasting or a fasting-mimicking diet inhibits mTOR.[ref]

A fasting-mimicking diet is one that reduces calories and

Getting a little deeper here, any conditions that decrease glucose and IGF-1 will reduce mTOR activity. Animal studies show that a ketogenic diet also inhibits mTOR.[ref]

5 Supplements for inhibiting mTOR:

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