Should You Take Experimental Life Extension Drugs?

And a blog essay on effective accelerationism and two podcasts

To my readers:

My output on my personal blog has been low lately. That’s largely because I’m pushing hard to finish a complete draft of my book on biostasis. If I can keep up the pace, I expect to finish a draft around the end of the year or in January 2025. The blog entries I have written have been on our group blog for Biostasis Technologies. Subscribers will probably enjoy my October 29 entry:

Effective Accelerationism and Biostasis

I look at the origins of effective accelerationism (e/acc) and its unacknowledged roots in extropian transhumanism as well as in several Singularitarian writers. Noah Smith has noted the “extropian enthusiasm” of e/acc. The original essays by the e/acc founders can be difficult to distill down so I outline the basics of  e/acc and then survey the many flavors of accelerationism. I point out errors in e/acc’s contrast with transhumanism. That is followed by a critique of the injunction to “follow the will of the universe.” Despite errors and shortcomings I conclude that e/acc is more right than wrong. From the perspective of the central important of life extension, I outline what might be called long/acc or longevity accelerationism.

Recent podcast interviews I have conducted:

Thinking About the Future with Anders Sandberg

Anders Sandberg has been thinking both critically and creatively about the future for several decades. I first got to know him and his thinking in the early 1990s and found someone who vision was remarkably close to my own. In this interview, Anders talks about the work he did for almost two decades at the Future of Humanity Institute and continuing today at Sweden’s Institute for the Future.

I asked Anders what kind of idea we can have of the future in a century or two, how seriously we should take existential risks, the changing attitudes toward life extension, biostasis, and transhumanist ideas, building a human community across time, how people can secure a high quality cryopreservation, and more.

Robin Hanson on cryonics, future trends, AI and more

Robin Hanson, economist, former AI researcher, and prolific blogger, is the author of The Age of EM: Work, Love, and Life When Robots Rule the Earth, and The Elephant in the Brain: Hidden Motives in Everyday Life. In this podcast with Max More, Robin tells us about:

• Why he made cryonics arrangements

• How prediction markets have developed since he came up with “ideas futures” in the 1990s

• What we can know about the future where biostasis patients are revived

• To what extent we should worry about AI displacing or harming humans

• Why we should be concerned about population decline

• And much more!

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Should you take Rapamycin?

I found Gary Taubes’ book, Good Calories, Bad Calories fascinating and pleasingly incisive in its examination of historical dietary recommendations and where they went wrong. Taubes is the author of several books including Good Calories, Bad Calories, Why We Get Fat: And What to Do About It, Rethinking Diabetes: What Science Reveals About Diet, Insulin, and Successful Treatments, The Case Against Sugar, The Case for Keto: Rethinking Weight Control and the Science and Practice of Low-Carb/High-Fat Eating,

I want to make a few comments on a recent post by Taubes on rapamycin.

Taubes notes that “the longevity movement” has become “the hot topic” and that rapamycin is much discussed in that movement. This seems to be true although I have seen more discussion recently of metformin, resveratrol, NAD+ precursors, and to a lesser extent Alpha-Ketoglutarate (AKG). Researchers and influencers, he says, are “no longer talk about treating or preventing chronic diseases, but about extending the span of a life without these disorders – the healthspan.”

Before Rapamycin came along, living a healthy life was about avoiding doing damaging things rather than what we do. “What these articles tend not to say is that the idea of taking a pill or any compound in any form to delay aging is new territory for medical science.”

It is true that much of being healthy consists of not doing unhealthy things – not smoking, not drinking excessively, not eating unhealthy foods or too much of any food. But even conventional wisdom advocates doing some things actively, most obviously exercising. (This exception will be important in relation to another point that I will get to.) The statement about “new territory” is surprising given the long history of pills and compounds and other treatments to delay aging. I mentioned some of this history on my essay on Biostasis as Longevity Plan A. Examples include Gerovital-HC (procaine), cellular therapy, hormone therapy, chelation therapy (EDTA), L-Dopa, lergotrile and other ergot derivatives, nucleic acid therapy, alpha Lipoic Acid, CoQ10 (ubiquinol), DHEA, melatonin, N-Acetyl Cysteine, metformin, NAD+, Dasatinib, quercetin, and resveratrol.

More plausibly, Taubes singles out rapamycin because “with its few decades’ worth of suggestive literature, is the first viable approach to increasing longevity that comes in pill form while simultaneously escaping, at least so far, the pungent aroma of snake oil that wafts over all other prospects.” Rapamycin is popular with many experts and is backed by considerable research, so wouldn’t it be foolish not to take it, asks Taubes. He quotes Seth Godin, “if you wait until you are ready, it is almost certainly too late,” then asks whether this logic applies to rapamycin. If we wait for conclusive evidence for effectiveness and safety, it may be too late.

Rewards, risks, prevention, and cures

Taubes briefly surveys the extent of the research, including its approved use in transplant patients, and two decades of research showing life extension in yeast, worms and fruit flies to mice, and rats as well as current testing in dogs. Life appears to be extended in these animals by 105 to 20%. Given the lack of published evidence in anything larger than a rat, Taubes uses 10% for his discussion. “Instead of dying at 80, say, you die at 88 and the drug delays by the better part of a decade every chronic disease diagnosis and every medical intervention you might receive in response. It might keep your immune system 10 percent younger, which could be critical for fighting off an infection.”

Perfectly reasonably, Taubes asks: Even if the benefits are real in humans, what are the risks? Is it a Faustian bargain? Any bioactive and non-native compound is likely to bring some harms.

In his view, we must make a sharp distinction between preventive medicine and curative medicine. With curative medicine we give a treatment that will have downsides because, without it, the patient will die. A patient hoping to live longer does not face significant medical consequences. A physician’s first obligation is the Hippocratic oath: Do no harm. For transplant patients, that means prescribing rapamycin. But that’s not true for healthy patients. In healthy patients being given preventive medicine to let them live longer, “The only relevant symptom of those who take a drug to extend their lifespan is that they are indeed aging—i.e., mortal.” In preventive medicine, “any risk of harm can be considered excessive.”

This is the first major point where I differ.

I grant that it is legally safer and reputationally reasonable for physicians to refrain from recommending a preventive measure that is likely to have bad side effects. But the distinction cannot be maintained in any rigid way even if we consider only standard treatments that are not typically labeled as “life extension.” Doctors commonly urge their patients to exercise.  But exercise can and frequently does have unwanted effects, from repetitive motion injuries, to broken bones and torn ligaments. Overall, the effects are expected to be beneficial and doctors prescribing exercise should first ensure that the patient is ready for it. But the unwanted effects are real risks. Therefore, Taube’s tidy distinction cannot be maintained.

Another example – one very relevant to Taubes’ own work – is dietary recommendations. Doctors and health experts often recommend specific diets. Taubes himself recommends low-carbohydrate and ketogenic diets. While strict diets can bring major health benefits they may also increase some risks. Which diets do that and how much is a matter of controversy. The point is that doctors recommend changes in diet that could lead to unwanted side effects. They do so because the expect the overall health outcome to be positive.

The distinction between curative and preventive medicine is plausible to a degree but fails to stand up in the end. Taubes does not count harm from death as a natural process as a negative. Therefore, not taking something that is expected to extend your life is the right thing to do if there might be any harmful side effects. But it does not matter that the cause of death is “natural.” It is a matter of risk vs. reward. Aging can be regarded as a disease or set of diseases or pathologies and it kills us more reliably than cancer or heart disease or any specific disease. Life extension medicine is curative.

Mikhail Blagosklonny, author of the opinion article “Rapamycin for Longevity,” is far more bullish. He says that, “If used properly, rapamycin is not much more dangerous than ordinary aspirin.” “Not taking rapamycin may be as dangerous as smoking.” And: “In conclusion, the side effects of rapamycin are well-known and reversible. When used on an anti-aging schedule, side effects may be absent but, if not, they may be mitigated by combining rapamycin with other anti-aging drugs (metformin, statins) or by temporarily discontinuing it.”

How can we know the long-term outcomes?

To be clear, I am not judging whether Taubes or Blagosklonny is more right about the benefits vs. risks of rapamycin. I agree with Taubes that, most likely, randomized trials are unlikely to be done. The testing in dogs may tell us more but we cannot be sure the results extend to humans. Taubes is also right to say that, even if rapamycin improves health in the short run, we have no guarantee that the benefits will not be outweighed by the harms over time. We should absolutely be cautious in taking a substance not well tested in humans. But we should not avoid it simply on the basis that it is preventive rather than curative or that there are risk.

Taubes highlights the difficulties of determining whether continued good health is due to taking a substance such as rapamycin or whether health would have been as good regardless. Unfortunately, Taubes does not consider biomarkers or aging or aging clocks such as GrimAge, an epigenetic age test that predicts biological age based on DNA methylation. Personally, although I find these tests fascinating, I am not yet convinced that they are a solid independent measure of aging. Even so, if they work out, they are a way of gaining knowledge much faster than waiting for a lifetime.

Subtraction vs. addition

Taubes quotes British epidemiologist Geoffrey Rose who distinguishes between two types of preventive measure. The first kind of preventive measure consists of the removal of an unnatural factor and the restoration of `biological normality’—that is, of the conditions to which presumably we are genetically adapted.” These measures can be presumed safe and so can be advocated for “on the basis of a reasonable presumption of benefit.” Taubes says this is he can recommend paleo diets and carb-restricted diets – because they “restore biological normality by removing the foods that are relatively new to human diets and to which we have not had time to genetically adapt.” I agree that this is a reasonable and plausible approach.

The second type of preventive measure “consists not in removing a supposed cause of disease but in adding some other unnatural factor, in the hope of conferring protection.” This increases biological abnormality. All pharmaceuticals are of this type, including rapamycin. “For such measures as these the required level of evidence, both of benefit and (particularly) of safety, must be far more stringent.” I think this is largely correct. It does not mean that the risk/reward equation cannot come out in favor of such a type-2 preventive measure.

Your personal risk vs. reward calculation

Two other points are missing in Taubes’ consideration of risk vs. reward. He notes note that a 10% increase in (healthy) lifespan would be “only” 8 years and that the treatment can (very likely will) have some unwanted side-effects. This impressive and yet still limited potential benefit may not make it worth taking the risks. But different people will rationally come up with different answers. Younger people should probably be discouraged from taking substances such as rapamycin. They have decades to develop problems that are not immediately apparent. Since rapamycin apparently works well when started later in life, it makes sense to wait.

If you are 60, or 70, or 80, the downside risk – given the considerable existing evidence – is small. We typically see young people as the risk takers and older people as more conservative and risk averse. In the case of a life extending treatment, this presumption should be reversed. It makes sense for older people to take more risk since they have less to lose with a life extension treatment.

Adding to that point, Taubes also does not consider the idea of “longevity escape velocity” -- a recent term for a idea that's been around for 50 years. The idea is that improvements in longevity treatments will accelerate so, if you can gain an extra 10 years, that may get you to a better treatment that can give you another 10 or 20 years. In that case, the gain of 8 years is potentially much greater.

Many people think we are at that point on the longevity curve. I thought so 40 years ago but find it highly unlikely -- unless, maybe, AI can accelerate biological understanding and intervention. For someone in their 20s or 30s it becomes more plausible but still highly uncertain. But I do think we will be up this accelerated upward curve in longevity at some point. It will very likely be too late for me. (Hence I have arrangements to go into biostasis.)

Not only does being older shift the balance of the risk/reward decision towards taking a promising compound, the balance shifts further the closer you think we are to making further gains in longevity.

Given his critical thinking about nutrition I was a little disappointed that he did not give more positive consideration to potentially life extending treatments. However, his discussion is more nuanced and contains more wisdom than most critical discussions.

Note: Taube’s writing will be moving to a new, personal blog, Uncertainty Principles.