The medication rapamycin seems to defy
logic. It boosts the immune system’s ability to fight cancer, but it might also
induce cancer. It prevents bacterial infection and stops viral multiplication,
albeit at the cost of immune system suppression. Although it slows the
progression of Alzheimer’s disease, it does increase the amount of plaque in
the brain. However, it also produces type 2 diabetes and improves metabolic
function. This list of inconsistencies could go on forever, but experts do
agree on one thing: rapamycin has the potential to be the most effective
anti-aging medicine ever found. Rapamycin has had a string of bad luck,
unfortunately.
Rapamycin as an antifungal
Chile’s government considered constructing
an international airport on Easter Island in the 1960s. Stanley Skoryna and
Georges Nogrady, two Canadian scientists, saw this as an excellent chance to
compare and contrast life on the island before and after the airport was built.
Skoryna and Nogrady collected soil samples from various parts of the island to
characterize the diversity of microorganisms, in addition to conducting
detailed physical exams on most of the island’s population of around 1,000
inhabitants. In the end, Skoryna’s and Nogrady’s efforts didn’t amount to much
in the way of scholarly advancement. Surendra Sehgal, a senior researcher at
Ayerst Pharmaceuticals (now Pfizer), came into possession of their soil
samples.
A novel antifungal chemical was discovered
in the soil samples in 1972 by the Ayerst team led by Sehgal. The Polynesian
name for Easter Island is Rapa Nui, so the property was given that name in
honor of the island.
The antifungal effects of rapamycin were
only temporary. It didn’t take long for Sehgal and his team to figure out that
rapamycin inhibited the formation of immune cells, which was problematic for a
patient who was trying to fend off an infection. Because of the drug’s
immunosuppressant classification, its antifungal use was discontinued.
Rapamycin as anti-cancer
Sehgal had no plans to abandon rapamycin
just yet. Following a hunch, he had a sample submitted to the NCI to check for
cancer-fighting properties. Cancer treatments that inhibit the immune system
tend to be ineffective. In fact, the FDA mandates that labels on most
immunosuppressants include a warning that they raise cancer risk. Cancer cells
are eliminated by the immune system. Therefore, cancer risk rises when the
immune system is weakened. Seghal was right in his suspicions, though; tests
showed that rapamycin inhibited the expansion of cancer cell lines like no
other medication had before.
All chemotherapies prior to the 1980s were
cytotoxic, meaning they killed healthy cells along with the cancerous ones.
This has devastating consequences since it results in the death of normal
cells. However, rapamycin was found to be cytostatic in the NCI’s testing,
meaning that it inhibited cell division without killing the cells themselves.
The implications of this finding for cancer treatment were enormous. Rapamycin
was rapidly progressed by NCI as a top-priority medication. More bad luck fell
upon the drug, unfortunately.
Ayerst terminated 95% of its personnel
while researchers and university scientists prepared for clinical trials of
rapamycin. Despite rapamycin’s promise, the study was halted. Sehgal, though,
was not willing to give up that easily. He brought some of the bacteria that
produced rapamycin home and froze it, where it stayed for six years.
Resurrection
New leadership came over after the 1987
merger of Ayerst and Wyeth. Sehgal successfully persuaded them to resume
studying the drug’s anticancer properties. After its resurgence, multiple
studies demonstrated that rapamycin inhibits cell proliferation across a wide
range of organisms, including fungi, plants, and animals. These inhibitory
effects varied between species, but rapamycin’s observed wide-ranging cellular targeting
provided evidence for its action via an evolutionarily significant master
regulator. This allowed for the discovery of mTOR, a protein critical for cell
division that was the subject of ground-breaking research in the 1990s.
Since its discovery, mTOR has been shown to
regulate a complex signaling network that regulates practically all facets of
growth and metabolism. Amino acid, glucose, insulin, leptin, and oxygen levels
all play a role in mTOR’s decision about whether cells should grow. This
evaluation is essential. A cell will perish if it tries to replicate without
first receiving enough nutrition, for instance.
Rapamycin has been used by millions of
patients since it was approved by the FDA for use in organ transplant patients
in 1999, following the discovery of mTOR. Its immunosuppressive properties
protect donated organs from rejection, and its low toxicity makes it
well-tolerated by patients. Researchers found that individuals who received
transplants and took rapamycin had a significantly lower risk of acquiring
cancer. The drug rapamycin was, at last, getting some well-earned recognition.
Rapamycin had one last unfortunate turn of events.
Scientist Surendra Sehgal, who never gave
up hope for rapamycin, was diagnosed with advanced colon cancer in 1998. In
those days, the average person with colon cancer lived for only 14.4 months.
When the cancer spread to his liver, his doctor started treating him with a
rapamycin analog, and the tumors in his liver stopped growing. Five years after
his diagnosis, he passed away in 2003. In 2004, a rapamycin analog was given
the green light for use against kidney cancer.
Rapamycin as anti-aging
As several labs tried using rapamycin and
its analogs to inhibit mTOR’s activity, they found that the medicine
significantly increased the longevity of both fungus and animals. Mice were
given rapamycin as part of the Interventions Testing Program at the National
Institute on Aging to determine the drug’s effects on longevity. The findings
caused a stir when they were published in 2009: Rapamycin prolonged the lives
of mice by six months, which is around 20 years in human terms.
After observing rapamycin’s anti-aging
properties in mice, researchers moved on to testing it in other animals,
including humans. Results from research involving 200 elderly people who took a
tablet containing a placebo or one of three dosages of a rapamycin analog
(everolimus) for six weeks were published by Novartis in 2014. Researchers
wanted to know if rapamycin improved the health of the elderly, but they didn’t
want to wait decades to find out if the treatment group survived longer.
As we become older, mTOR becomes
overactive, leading to more effort from the immune system (and probably other
systems as well). Researchers hypothesized that suppressing mTOR activity would
improve immunological function in study subjects. After six weeks of treatment,
the researchers vaccinated all of the subjects against influenza and evaluated
their immune responses. The lowest dose of everolimus resulted in the highest
levels of flu antibodies in the blood, showing that it enhanced the immune
system function of the subjects.
Immune system rejuvenation
The fact that rapamycin, an
immunosuppressant, can also improve immunological function may appear to be at
odds with itself. However, rapamycin was classified as an immunosuppressant at
a time when researchers knew very little about the mechanisms that control the
immune system. Rapamycin, when given in small dosages, “rejuvenates
immunity,” reducing the effects of hyper-immunity while leaving healthy
immunity unharmed. Rapamycin would have been more enticing if it were called an
immunomodulator or anti-inflammatory medicine.
Rapamycin has a bad rep for raising cancer
and infection risks because it was wrongly grouped with other
immunosuppressants. However, research has shown that rapamycin reduces the risk
of lymphoma and other cancers in transplant recipients and increases their
resistance to infections. The lack of a healthy placebo group in many studies
is a major contributor to the overestimation of the frequency of rapamycin side
effects. Fortunately, this is starting to alter. There were no adverse effects
from the placebo group in a study of healthy older persons. Researchers at UCLA
launched a three-year research examining the longevity benefits of rapamycin
and its safety in healthy older persons in 2020.
