All of PhilJackson's Comments + Replies

  1. Indeed - people are finally thinking "what if ageing has something to do with all the age-related disease?" This is great, so long as you remember that "ageing" is not just one single root cause of age-related disease; rather, it's a multitude of self-inflicted injuries the body slowly accumulates, which combine to make us frail and disease-prone. 
  2. Simulations of that fidelity level would indeed be ridiculously powerful tools, but I don't know how long it'll take to reach that level. Also, with a true full-body molecular simulation you'd have the ethic
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The Senolytics section comes across a bit like all senescent cells are bad so if we could just kill them all we'd be doing a good thing. But my understanding is that they also play a role in healthy body functions. Is that also your understanding here?

From what I've read, the healthy roles they play are a) during early/embryonic development and b) in wound healing. So, don't give senolytics to embryos or people healing from wounds I guess. Also, there's a paper (summary here) showing that it's possible to regain the wound-healing benefit of SCs in mice tha... (read more)

100% agree the messaging should focus on health rather than lifespan - not only because it's far less controversial (most people want to be healthy), but because it's true: we work directly on health, of which longevity is but a side effect. Glad you picked up on the multi-morbidity part too, tackling age-related sickness as a whole by focusing on fundamental ageing damage rather than treating diseases separately is crucial. Probably we'll be talking about morbidity compression for a while yet; this is a crux that allows us to discuss medicine that actuall... (read more)

1Kamil Pabis
While the term "healthspan" can be useful for public messaging it is not necessary to use it instead of "lifespan" as study after study shows. When the word "lifespan" is used in the correct context people are very willing to embrace even radical lifespan extension. It seems prudent to combine both concepts. Asked “If doctors developed a pill that enabled you to live forever at your current age, would you take it?” a surprising number of people turned out to be hardcore life extensionists: "There were no differences by age...Among young adults, 40.0% indicated they would not take the pill, 34.2% indicated they would take the pill, and 25.8% indicated they were unsure." Barnett, Michael D., and Jessica H. Helphrey. "Who wants to live forever? Age cohort differences in attitudes toward life extension." Journal of Aging Studies 57 (2021): 100931.

It's both prevention and cure - prevent disease by reversing damage before it gets bad enough to cause problems, but if you already have a chronic disease, then reversing the damage that causes it will be the only way to cure it (though prevention is better of course).

I agree the preventative medicine angle is a good one that people will buy easily, but you can make the same argument against it - that we've always been trying to prevent disease just as we've always been trying to fix damage. 

It's important to note that statins, blood thinners and rapa... (read more)

2DirectedEvolution
That’s a reasonable point of view. I don’t think we should be certain that the effects of rapamycin at high doses will be reflective of its effects at low doses, which is why we need to test it. This era is all about precision medicine, figuring out how to control dosing, release, and specific delivery in the context of much better knowledge of how these drugs affect the body to cut side effects and enhance benefit. The heuristic of leaning toward occasional damage repair by engineered interventions rather than continuous damage slowdowns by manipulating evolved biochemistry makes sense, but so does the heuristic of focusing on an available tool that we have extensive data works pre-clinically right now. I think the “don’t mess with evolution” heuristic is oversubscribed for antagonistic pleiotropy and declining selection pressure with age reasons when it comes to anti-aging medicine. All the same, I expect that over time we’ll come up with a wide range of both preventative and damage reversal interventions, perhaps along SENS lines. But in that context, a damage-slowing drug (perhaps rapamycin) that might reduce the frequency of the need for damage reversal therapies will be highly valuable, and particularly because it may well be the cheapest and most accessible option to get started, especially in countries that don’t yet have fully developed medical systems..

Always glad to see Greg Egan referenced. The important thing to me is that although population growth could be exponential (for the reasons cousin_it gave), it's going to be very slow relative to the rate of technological progress. Unless fertility rises significantly, it's likely to be hundreds of years before population would grow by 10x, by which point we're well into Greg Egan territory and all bets are off anyway. So population could be a concern, but we'll have plenty of time to address it via methods that don't involve literally everyone dying.

3Ilio
On second thought, strong upvote for this answer because I think it’s key to pinpoint our divergence. You think that we will likely be well into Greg Egan territory in a few hundred years, whereas new tools in biology are so fantastic we are a few decades to, yes immortality, but I guess you see that as a direct consequence of reaching biological universality (when we can basically at will make cells do whatever one cell can do). To me (and, in a sense, echoing Vladimir_Nesov´s comment above) that’s the contrary: not only I expect new biological limitations to show up nearly as fast as we solve old problems (like decoding the human genome was fantastic, and fruitful, but not as fruitful as I was naively thinking at the time), but I also fully expect we will taste Greg Egan territory several decades before we will fully master our own biology. Late late late disclaimer: I’m toying with the idea of starting a series of post called Road to amortality, so you should expect me to be biased and stubbornly attached to my ideas. 😉 To fight the latter, here’s one result that would move me toward your position: if we can print or grow any complex organ within the next decade. Do you accept this criteria as fair and to the point? Would you mind thinking of some results that would make you strongly update toward my position?

Yes we've always been trying to fix damage - anything that restores function must fix damage somehow - but it's a matter of what we consider to be damage, i.e. "bad stuff that we should try to fix because it would restore function". Historically we've focused on trauma, infection and cancer, and although we've known about age-related changes like lipofuscin accumulation for a long time, it's only recently that we started thinking of them as potential targets. Gerontology has historically been a field of basic science, with few gerontologists willing to ven... (read more)

4DirectedEvolution
Agreed, I like this elaboration. As I see it, the argument really is that we’ve been neglecting preventative medicine in favor of treating disease after it has become symptomatic. This is a familiar critique that normal doctors and laypeople already subscribe to, and showing that anti-aging medicine is really just another familiar form of preventative medicine (which we have historically neglected) will make more immediate sense than claiming that “we haven’t been fixing people’s bodies” which is only true in the specific sense you just articulated. Along with that is emphasizing that it’s normal and natural to use preventative medicine. You brush your teeth, you try to eat a good diet and get enough sleep and exercise, you might stake preventative statins or blood thinners or get LASEK. If you’ll do all these things to maintain your health, then why not take low-dose rapamycin? It’s really going to be about normalizing the use of pill-form preventatives at an earlier age, and breaking the association between pills and “being sick.” Instead, it’s about creating an association between pills and “maintaining health.”

If we define damage as material defects, which I think is closer to your original intent, then maladaptative memories (of the affective system in PTSD, of the pain system in CRPS, of the immune system….) can cause a loss of function without a lasting role for material damages

"Material"? I don't think it's useful to distinguish between material and immaterial change, the point is that the change is maladaptive. If your hard drive gets corrupted preventing your computer from booting then we still call that damage, even though it seems less material than, say... (read more)

You may well turn out to be correct - biology is indeed fiendishly complex and still very poorly understood, and it may turn out that clearing the damage types identified by the SENS platform is insufficient for comprehensive rejuvenation. However, I've tried to separate that particular claim from a different, more defensible, more immediately relevant one: that damage repair should become our main approach to medical research in a world where infectious disease is largely conquered, and most suffering is due to (mostly age related) chronic illnesses. Most... (read more)

2mruwnik
Totally agree and am glad you wrote this post

To me, damage repair is a first and foremost a new, fundamentally different approach to medicine, one that emphasizes fixing things that are obviously broken, which I expect to work much better than the old paradigm of treating diseases separately. The whole "ageing" thing is almost secondary to me. We've literally not been fixing people's bodies this entire time, and now people are finally trying to fix a bunch of obviously broken things, that's why I'm excited.

I like the parts of the post I've read so far, and I'm just making a local argument to this spe... (read more)

The one that always come to mind is: how will we spare space for the youths?

I'm unusually chill when it comes to population, both over and under. I'm not enormously concerned by how many people there are, I'm more concerned by how healthy the existing people are, and how healthy the environment is, both of which are mostly orthogonal to population and depend primarily on technological development. It's important to note that fertility rates are generally declining worldwide, seemingly in tandem with economic development. The most economically developed cou... (read more)

4cousin_it
Why would fertility per woman stay the same when childbearing lifespan is increased? It seems more likely to me that fertility per woman per year would stay the same - have a kid or two, then a few decades doing other things, then another kid or two and so on. And this leads to exponential growth (as long as fertility/woman/year > 0).
1Ilio
Is that really conter counter? Levin’s idea on long range communication fits well with the ideas of cancer as learning system, even better than natural selection alone. Also, the impact of diluting blood seems 100% compatible with the idea that it’s diluting an ageing marker (indeed inflammatory molecules are excellent candidates). These definitions are imho too forgiving.: if we define damage as loss of health, then sure « removing damage » will tautologically cause good health. If we define damage as material defects, which I think is closer to your original intent, then maladaptative memories (of the affective system in PTSD, of the pain system in CRPS, of the immune system….) can cause a loss of function without a lasting role for material damages (beside killing oneself when it’s no longer possible to cope with this level of pain|suffering)

There are papers showing senescent cells in humans with signs of shortened telomeres and replicative stress (e.g. [1,2]), so I wouldn't say the Hayflick limit is nonsense or irrelevant in humans. But there is perhaps a broader point that the Hayflick limit / telomere erosion has been over-hyped as the fundamental driver of ageing. Case in point, I once talked to a guy who told me "Immortality is impossible, because: telomeres". 

The problem is that telomere erosion tells a simple and compelling story about what ageing is, like every cell has a built-in... (read more)

Point taken. I guess the main difference for me is that with age reversal, we've got a framework that makes sense and de-mystifies it, and it implies that if we just do this and this and this and this then the problem should be solved. We can actually see a path between where we are right now and where we want to be. Do we have something like that with AGI, or is it more a matter of "these language models are starting to look pretty smart"? I'm not saying I would bet against AGI, the way things are going... but I wouldn't want to rely on it without a rational model of it, either.

5the gears to ascension
For what it's worth, as someone with incredibly short time expectation until we get the big one over in AI land, I don't think "ask agi to figure it out" is going to be how it feels to solve aging using agi. I expect it to look more like supercharging exactly this research plan you outline with extremely advanced bio simulation. And I expect that AI safety will look like biosecurity, in large part because I don't think it could possibly look another way - as ai advances it is looking more and more like a field of silicon biology.
5Vladimir_Nesov
Try this post. Basically, everything is too easy recently, with many roads leading to progress. And very recently, there are plausible roadmaps that don't require any new discoveries (which would otherwise take unknown amount of time), just some engineering. It's no longer insane (though not yet likely, I'd give it 8%) for AGI to be done in two years even without secret projects or unexpected technical breakthroughs. (By AGI I mean a point where AI becomes able to teach itself any skills that don't fall out of its low level learning algorithm on their own, but it hasn't yet learned much in this way.) Alignment looks relatively hopeless, but at the same time if AGI is something along the lines of ChatGPT, it's more likely to be somewhat human-like and possibly won't cause outright extinction, even if it takes away most of the resources in future lightcone that humanity could've gotten for itself if it was magically much better at coordination and took its time to figure out alignment or uploading.

Not all cells in the adult body do divide, most of them I think divide only rarely if ever. Cells that divide more regularly generally express telomerase to keep their telomeres from running out. Telomeres running out may still be an issue though, so there are people looking at ways of lengthening them via telomerase expression.