summarize this "Yet its autophagy-promoting effect is only one reason why rapamycin may
have a future as a longevity drug, according to Matt Kaeberlein, a researcher
at the University of Washington. Kaeberlein, who has been studying
rapamycin and mTOR for a couple of decades, believes that the drug’s
benefits are much more wide-ranging and that rapamycin and its derivatives
have huge potential for use in humans, for the purpose of extending lifespan
and healthspan.
Even though rapamycin is already approved for use in humans for
multiple indications, there are formidable obstacles to launching a clinical
trial to look at its possible impact on human aging—mainly, its potential side
effects in healthy people, most notably the risk of immunosuppression.
Historically, rapamycin was approved to treat patients indefinitely
following organ transplantation, as part of a cocktail of three or four drugs
meant to suppress the part of their immune system that would otherwise
attack and destroy their new organ. This immune-suppressing effect explains
why there has been some reluctance to consider using (or even studying)
rapamycin in the context of delaying aging in healthy people, despite ample
animal data suggesting that it might lengthen lifespan and healthspan. Its
purported immune-suppressing effects just seemed to be too daunting to
overcome. Thus, it has seemed unlikely that rapamycin could ever realize its
promise as a longevity-promoting drug for humans.
But all that started to change in late December 2014 with the publication
of a study showing that the rapamycin analog everolimus actually enhanced
the adaptive immune response to a vaccine in a group of older patients. In the
study, led by scientists Joan Mannick and Lloyd Klickstein, who then worked
at Novartis, the group of patients on a moderate weekly dose of everolimus
seemed to have the best response to the flu vaccine, with the fewest reported
side effects. This study suggested that rapamycin (and its derivatives) might
actually be more of an immune modulator than an “immunosuppressor,” as it
had almost always been described before this study: that is, under some
dosing regimens it can enhance immunity, while under completely different
dosing regimens it may inhibit immunity.
Until this study appeared, I (like many others) had largely given up on the
possibility that rapamycin could ever be used as a preventive therapy in
healthy people. I had assumed that its apparent immunosuppressive effects
were too serious. But this very well-done and well-controlled study actually
suggested the opposite. It appeared that the immune suppression resulted
from daily use of rapamycin at low to moderate doses. The study subjects had
been given moderate to high doses followed by a rest period, and this cyclical
administration had had an opposite, immune-enhancing effect.
It seems odd that giving different doses of the same drug could have such
disparate effects, but it makes sense if you understand the structure of
mTOR, which is actually composed of two separate complexes, called mTOR
complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The two
complexes have different jobs, but (at risk of oversimplifying) the longevityrelated benefits seem to result from inhibiting complex 1. Giving the drug
daily, as is typically done with transplant patients, appears to inhibit both
complexes, while dosing the drug briefly or cyclically inhibits mainly
mTORC1, unlocking its longevity-related benefits, with fewer unwanted side
effects. (A rapamycin analog or “rapalog” that selectively inhibited mTORC1
but not mTORC2 would thus be more ideal for longevity purposes, but no
one has successfully developed one yet.)
As it is, its known side effects remain an obstacle to any clinical trial of
rapamycin for geroprotection (delaying aging) in healthy people. To get
around these objections, Kaeberlein is doing a large clinical trial of rapamycin
in companion (pet) dogs, which are not a bad proxy for humans—they’re
large, they’re mammals, they share our environment, and they age in ways
similar to us. In a preliminary phase of this study, which he calls the Dog
Aging Project, Kaeberlein found that rapamycin actually seemed to improve
cardiac function in older animals. “One thing that’s been surprising to me,” he
says, “is the different ways that rapamycin not only seems to delay the decline
but seems to make things better. There clearly seems to be, at least in some
organs, a rejuvenating function.”
Kaeberlein has also observed that rapamycin seems to reduce systemic
inflammation, perhaps by tamping down the activity of so-called senescent
cells, which are “older” cells that have stopped dividing but have not died;
these cells secrete a toxic cocktail of inflammatory cytokines, chemicals that
can harm surrounding cells. Rapamycin seems to reduce these inflammatory
cytokines. It also improves cancer surveillance, the ways in which our body,
most likely the immune system, detects and eliminates cancer cells. In
another recent study, Kaeberlein’s group found that rapamycin appeared to
improve periodontal (gum) health in older dogs.
The main phase of the Dog Aging Project, involving some 600 pet dogs,
is now under way; results from this larger clinical trial are expected in 2026.
(Disclosure: I am a partial funder of this research.) The dogs in this study are
also following a weekly, cyclical dosing schedule with rapamycin, similar to
the protocol in the 2014 immune study in humans. If the results are positive,
it would not surprise me if the use of rapamycin for longevity purposes
becomes more common. A small but growing number of people, including
me and a handful of my patients, already take rapamycin off-label for its
potential geroprotective benefits. I can’t speak for everyone, but taking it
cyclically does appear to reduce unwanted side effects, in my experience.
Even so, the hurdles it would have to clear to gain approval for broader
human use remain daunting. The vast majority of people who currently take
rapamycin comprise transplant patients who already have serious health issues
and multiple comorbidities. In populations like this, rapamycin’s side effects
seem less significant than they might in healthier people.
“There is a very low tolerance for side effects, by the public and by
regulatory agencies, if you’re talking about treating a healthy person,” says
Kaeberlein. “The intent is to slow aging in people before they get sick, to
keep them healthy longer, so in many ways it is the opposite of the traditional
biomedical approach, where normally we wait until people are sick and then
we try to cure their diseases.”
The real obstacle here is a regulatory framework rooted in Medicine 2.0,
which does not (yet) recognize “slowing aging” and “delaying disease” as fully
legitimate end points. This would represent a Medicine 3.0 use for this drug,
where we would be using a drug to help healthy people stay healthy, rather
than to cure or relieve a specific ailment. Thus, it would face much more
scrutiny and skepticism. But if we’re talking about preventing the diseases of
aging, which kill 80 percent of us, then it’s certainly worth having a serious
conversation about what level of risk is and isn’t acceptable in order to
achieve that goal. Part of my aim in writing this book is to move that
conversation forward.
This may already be starting to happen. The FDA has given the green
light for a clinical trial of another drug with potential longevity benefits, the
diabetes medication metformin. This trial is called TAME (Targeting Aging
with Metformin), and it came about in a very different way. Metformin has
been taken by millions of people for years. Over time, researchers noticed
(and studies appeared to confirm) that patients on metformin appeared to
have a lower incidence of cancer than the general population. One large 2014
analysis seemed to show that diabetics on metformin actually lived longer
than nondiabetics, which is striking. But none of these observations “prove”
that metformin is geroprotective—hence the need for a clinical trial.
But aging itself is difficult—if not impossible—to measure with any
accuracy. Instead, TAME lead investigator Nir Barzilai, whom we met in the
previous chapter, decided to look at a different endpoint: whether giving
metformin to healthy subjects delays the onset of aging-related diseases, as a
proxy for its effect on aging. I’m hopeful that someday, maybe in the near
future, we could attempt a similar human trial of rapamycin, which I believe
has even greater potential as a longevity-promoting agent.
[*3]
For the moment, though, let’s think about the fact that all of what we’ve
talked about in this chapter, from mTOR and rapamycin to caloric restriction,
points in one direction: that what we eat and how we metabolize it appear to
play an outsize role in longevity. In the next chapter, we will take a much
more detailed look at how metabolic disorders help to instigate and promote
chronic disease.
"