I try to be selective when I provide an opinion. Occasionally circumstances arise whereby opining may do overall good.
Recently a member of the Twitter community has publicly declared he has metastatic cancer. This individual has also been on high dose rapamycin.
So I have been asked, as someone who has expressed enthusiasm for pursuing translational research whether benefits in animal models extend to people, does this news change my mind?
No, not one bit
Case reports are uninformative regarding causality.
We already know cancer is possible on rapamycin, this is not new.
Cancer is stochastic- I have shared data on risk factors because I believe knowing them empowers us to reduce risks. This is NOT the same as cancer elimination. Chance (and unknown, often stochastic risks( will always play a role. Risk is never zero.
Indeed as physicians when we tell patients they have cancer and they ask why, most often we can share information on risk factors but usually not why they got cancers. Because we do not know, and it generally/usually for practical purposes unknowable.
Model organisms on rapamycin still die. We all do. They just die, on average, later and as far as we can tell in overall better health (except the end).
What what do mice, etc on rapamycin die from? In large part the same conditions that are fatal in control animals.
The difference in life expectancy between rapamycin and control mice is an average. Some mice live shorter as well as longer. The differences in lifespan is an average. Simply put, being in rapamycin stacked the deck (odds) in favor of a longer lifespan.
Back to chance: Mr Rogers was slim and ate his vegetables. Yet he died young, of cancer. Shall we blame his being slim or minding his diet? Or that until the end he had a very disciplined swimming routine? No- case reports simply are not informative in this manner.
These arguments can be extended to other agents too, say individuals taking derivatives of niacin for example. Unfortunately we are mortal, and will see the full gamut of pathology sometimes regardless of our best efforts. Our job is to take the best evidence, respond to data & make our best efforts to follow the evidence and our best chances for good health.
Rapamycin, additionally has data in both animal models and humans. The human data mostly favors less cancer compared to patients on other transplant medicine. To the extent the human data is mixed in some places, the quality is poor, based on patients who are generally already sick (having transplants, being on other meds including immunosuppressants etc) and also on a very particular high dose daily regimen to boot.
We do not have good, reliable data for humans. Apparent outcomes in community based off-label prescribing for geroprotection has if anything been mostly reassuring. To truly understand the relationship of rapamycin with human health we need more, better, rigorously controlled trials. Thus poor data only makes the case stronger for translational research in people. This, and the strong and reliable independently validated and reproducible lifespan extension seen in model organisms compel this research more than ever.
Finally, it should be noted that not only do animal models at physiologically relevant doses tend to have cancer later in life, but even in humans rapamycin and related rapalogs are being used as an adjunct in the treatment of several human cancers.
Though not a cure, human data suggesting extended relapse free survival for some cases is more a source of hope than concern. Indeed, I am aware of no well conducted RCTs in humans that even very high dose rapamycin (10+ mg per DAY) shortens lifespan vs usual care in cancer patients.
Precisely because of animal models and some suggestive data in humans, several low dose rapamycin prevention trials have been proposed.
I believe these, and many more should be done. A major point of animal models is to save us time and resources and allow for highly controlled feasible rigorous study design. The results of this suggest when agents warrant our attention.
I believe that rapamycin warrants such attention, as the highest effect size (magnitude of life extension) and highly reproduced small molecule intervention in normal, healthy, and genetically diverse, naturally aged mice. So too for a plethora of other model organisms too, not to mention validated in rodents of both genders.
Unknowns are not a reason to avoid investigation. They are inevitable. And all our choices of have potential risks and reward.
Rather, promising data and unknowns are a reason for investigation.
With unknowns cons risks… but also potential benefits. This is how we learn. Science is not s religion. We do not have “faith” in a molecule or intervention. We must test it. We study it, and we follow the data wherever it takes us. Both the good and the bad. We must test our theories to determine where we were right, where we were wrong, and where to go next.
This is our way forward. I support geroscience research and all promising work towards improving our health. I will support research in any promising area with potential to improve our health, and am committed to following the data, wherever it takes us, and always with an open and adaptive mind, as new data and evidence present themselves.
Not all seemingly promising interventions will ultimately work out- and most will not, sometimes at a great cost - but we must nevertheless roll up our sleeves and do the actual work to determine which ones.
We all face sickness or decline and death. Marching ahead is how we make progress. We have left the jungle and created civilizations and modern medicine. We still have far to go. Our limits are only defined by physics, our inherent but expanding capacity, and perhaps most of all the time and commitment to prioritizing progress central to elevating our healthspan and quality of life.
So where do we stand now? Progress depends on US. Our reason, our time, our resources- and our commitment.
From these data to date, more than ever, I still believe there is a strong case for vigorously supporting rapamycin trials, without delay.
I came to Twitter was to do good. Among them I saw an opportunity around drawing attention to rapamycin, which I regarded as having the greatest potential for being validated as a potent healthspan extender in suitable candidates. I felt if it held up to it’s promise, it has the potential to not only be an n exiting target for aging biology, but more fundamentally and profoundly, and across the world a true game changer toward better public health.
That was my hope; an inspiration of what might be possible.
After all this time, how has my feeling changed about this and rapamycin?
Not one bit.
