Suppressing mTOR

It sounds like science fiction. Bacteria in a vial of dirt taken from a mysterious island create a compound that prolongs life—and not just in the traditional medical sense. Thanks to advances in modern medicine, we are living longer lives, but we’re doing so by lengthening the morbidity phase. In other words, we are living longer but sicker lives. Traditional medical approaches tend to just increase the number of old people in bad health. Ideally, though, we’d extend lifespan by slowing aging. That way we could delay the onset of deterioration, rather than just extend the period of deterioration. That’s exactly what this new compound appeared to do.

Researchers called it rapamycin, named after the bacteria’s home––the mystical Easter Island famed for its rock-carved figures, which is known locally as Rapa Nui. Rapamycin inhibits an enzyme that’s come to be known as mTOR, or “mechanistic target of rapamycin,” a key modulator of aging, characterized as a “master determinant of lifespan and ageing.”

What does the enzyme mTOR actually do? It is the major regulator of growth in animals. Activation of mTOR drives increases in both cell size and cell number. What’s wrong with that? The action of mTOR has been described as the engine of a speeding car without brakes.

In this analogy, aging is a hurtling car that enters the low-speed zone of adulthood and damages itself, because it does not and cannot slow down. We are over the hill and picking up speed. Why don’t living organisms have brakes? Because they’ve never needed them. In the wild, animals often don’t live long enough to experience aging. Most animals die before they even reach adulthood. The same used to be true for humans. Due to early age mortality, in the 17th century, most Londoners didn’t even make it to age 16.

So, living beings need to grow as fast as possible to start reproduction before they die from external causes. The best evolutionary strategy may therefore be to run at full speed. However, once we pass the finish line, once we win the race to pass on our genes, we’re still careening forward at an unsustainable pace––all thanks to this enzyme mTOR. In our childhood, mTOR is an engine of growth. But in adulthood, it can be thought of as the engine of aging. Nature simply selects for the brightest flame, which in turn casts the darkest shadow.

This is the so-called trade-off theory of aging, a concept technically known as antagonistic pleiotropy, in which a gene can have a positive effect when young, but a negative effect when old. This explains how genes with deleterious effects late in life can persist in a population. For example, the pro-inflammatory “Alzheimer’s gene” appears to protect against childhood infections––a major killer throughout most of human existence.

What’s the downside of unconstrained growth fueled by mTOR? The enzyme plows full steam ahead, revving up construction pathways to churn out cellular building blocks for new growth, which can include cancerous tumors, while canceling any renovation or demolition. To preserve growth at all costs, mTOR actively suppresses autophagy, countermanding cellular cleansing and rejuvenation. In my autophagy chapter in How Not to Age, I explain how this can lead to accelerated aging. Conversely, slowing things down by putting the brakes on mTOR appears to decelerate the aging process, extending life and health. Inhibiting mTOR is considered the best-validated aging regulator.

The soil bacteria on Easter Island weren’t making rapamycin to slow down aging, but rather to slow down the growth of its natural enemy, soil fungi (just like fungi make penicillin to wipe out competing bacteria). Fungi from yeast on up, like all plants and animals, have mTOR genes. This target of the rapamycin enzyme is the universal growth regulator of advanced lifeforms. So, while rapamycin originally drew attention as an antifungal drug, we soon learned it had many other effects.

Dozens of published studies have demonstrated that rapamycin, by slowing down mTOR, extends both the average and maximum lifespans of laboratory mice. In fact, rapamycin appears to be a universal anti-aging drug, extending the lifespan of all animals and organisms tested to date—the only known drug to do so. It can even work when started in midlife.

The original National Institute on Aging Interventions Testing Program experiment in 2009 was delayed because the researchers were having difficulty keeping rapamycin stable in the mouse food pelleting process. (It can’t just be dissolved in their drinking water because it’s fat soluble.) By the time they were up and running, the allotted batch of mice were 600 days old, which is equivalent to about 60 years of age in humans. Even though the mice started the drug so late in life, their lifespans were still extended by about 12 percent, which could equate to more than an added seven years of human life.

Initially, it was debated whether rapamycin was a true anti-aging intervention or “merely” a potent anticancer agent, lengthening lifespans by just preventing cancer formation. mTOR signaling is hyperactive in up to 80 percent of human cancers, where it plays a pivotal role in sustaining tumor growth. Rapamycin is used clinically to prevent the rejection of organ transplants (by suppressing the proliferation of immune cells that attack the new organ), and a peculiar side effect was found. In a set of 15 patients who had biopsy-proven Kaposi’s sarcoma (a cancer that often affects the skin), all sarcoma skin lesions disappeared in all patients within three months after starting rapamycin therapy. The cancer just vanished. As TOR is the master regulator of cellular growth, the cancer remission was not completely unsurprising, but subsequent rapamycin studies showed it can do so much more.

In animal models, rapamycin extends healthspan too. Rapamycin can ameliorate age-related declines in cognitive function and physical function, prevent hearing loss, artery dysfunction and tendon stiffening, regenerate the periodontal bone that holds teeth in place, and even rejuvenate the hearts of aged mice. Remarkably, health and longevity benefits could be achieved with intermittent or transient dosing, like getting one dose every five days, or for just a few months during middle age.

As a dog dad, I was excited to read about the Dog Aging Project, where people brought their middle-aged companion canines to be randomized to low-dose rapamycin or placebo for 10 weeks. Like in the mouse studies, rapamycin appeared to at least partially reverse some of the age-related heart dysfunction without any untoward side effects. Anecdotally, most of the owners of the dogs who covertly got the rapamycin reported their dogs displayed increased activity and energy compared to only a minority of the owners of the pooches slipped the placebos.

It was time to try rapamycin out in humans, which I’ll cover next.

In Alzheimer’s brains on autopsy, markers of mTOR activation have been found to be as much as 100 times higher than age-matched brains of those dying from other causes. That makes sense, since nerve cells rarely divide once they reach maturity, which would otherwise dilute damaged cell debris. Autophagy is particularly important in the brain. Given the “striking” improvement in cognitive function in old mice from the mTOR blocker rapamycin, and studies showing the prevention (and possible restoration in some cases) of memory defects in transgenic mouse models of Alzheimer’s disease, there have been calls for clinical trials of rapamycin for Alzheimer’s patients.

After all, mTOR regulates Alzheimer’s biggest risk factor––aging itself. The risk of developing this dementia approximately doubles every five years after the age of 65, with the risk of death from Alzheimer’s skyrocketing approximately 700-fold from age 55 to 85. Unfortunately, no such clinical trial has been attempted. It doesn’t even look like the dementia rates of organ transplant patients given rapamycin have ever been tracked. When kidney transplant patients are initially switched to mTOR inhibitors, they do seem to experience a significant improvement in executive function, memory, and mood, but that may in part be because they were switching from drugs like cyclosporine which can, on their own, cause adverse neuropsychiatric effects.

Rapamycin has been off-patent for more than a decade; so, drug companies can no longer charge whatever they want. Without such price protection, there isn’t a strong profit motive to study the drug. So, we shouldn’t expect any large clinical trials any time soon. Another reason for clinical trial hesitancy may be the frequent, and sometimes life-threatening, side effects––like immunosuppression. In one cancer trial of an mTOR inhibitor, for example, two of the eighteen patients developed life-threatening infections, and one of them died. To fight cancer or organ rejection, we may be willing to put up with significant risk. But there’s a much lower risk tolerance for anti-aging drugs meant to be used en masse for healthy humans.

The mouse longevity trials are impressive, but they’re typically performed in a strictly controlled pathogen-free environment that may not translate out into real world conditions. The immunosuppressive effects alone are considered sufficient to caution against self-experimentation. Nevertheless, there is a clinic devoted to patients who self-medicate with rapamycin in an attempt to slow aging. Rapamycin advocates point out that the doses required for anti-aging are much lower than used in cancer therapy or organ transplantation, and, if anything, might rejuvenate immunity. Is it possible that transient and/or intermittent dosing could also help reap the benefits without as many risks? You don’t know, until you put it to the test.

Two small pilot studies of low-dose rapamycin for a few months in the elderly didn’t cause any major side effects (though did cause diarrhea in up to 62 percent), but also failed to find any immediate benefits to cognitive function or physical performance. In 2018, however, hundreds of individuals age 65 and older were randomized to mTOR inhibition about 100-fold lower than what’s used in oncology or transplant patients. And, instead of immune suppression, they did appear to get immune rejuvenation. Not only did they experience an improvement in their response to flu vaccination, but they experienced significantly lower infections in the subsequent year compared to placebo, and they only got the drugs for six weeks. This suggests a persistent improvement in immune function months after discontinuing the drug. Still, self-experimentation continues to be strongly discouraged until we have a better idea of the risks. Thankfully, there are ways to suppress mTOR without taking drugs.