The Fountain of Health: a First Principles Guide to Rejuvenation

post by PhilJackson · 2023-01-07T18:34:12.094Z · LW · GW · 38 comments

Contents

  What is ageing? 
  What is damage?
  You can’t stop it, but you can reverse it
  Stop treating disease, start fixing damage
  Primary damage, secondary damage
  AGI, Nanotechnology
  Why do we age?
  Ageing Clocks
  Examples
    Senolytics
    LysoClear
    Thymus Regrowth 
    Curing Atherosclerosis
  Combination Therapy
  Epigenetic reprogramming 
  Morbidity compression
  Longevity Escape Velocity
  The War On Ageing
  Conclusion
  About me
None
38 comments

I’d like to live in a world where age really is just a number. For the last ~3 years or so, I’ve been nerding out with increasing fervour about longevity biotech, having originally been inspired by one of Aubrey de Grey's many interviews. I want to explain how and why I've become optimistic about the short-term prospects of indefinite healthy life extension, in terms of how I've come to think about ageing, disease, medicine and rejuvenation.

A revolution is underway in how people think about health and medicine. Worst case scenario, it will unlock a whole new generation of therapies that can actually cure chronic age-related diseases, instead of just moderately slowing their progression at the expense of multiple poorly understood side effects. Best case scenario, it will enable us to live indefinitely in bodies that are functionally and cosmetically indistinguishable to those of 25 year olds. As with AGI, nobody can predict with certainty how long this will take, but optimism has grown tremendously over the past five years, and it is no longer unusual to encounter experts who believe that the ageing process is malleable. 

This timeframe depends massively on how rapidly we can divert funding and talent toward longevity biotechnology, because we are not going to achieve this outcome by doing more of what mainstream biomedicine has been doing. You could liken our position to where SpaceX are right now on the road to Mars: there's a long way to go still, but no Nobel prizes are required, no major scientific breakthroughs, just a lot of engineering. In this post, I will explain what ageing is, why we suck so much at treating chronic illnesses, and how this problem will be solved by a new kind of medicine, one that directly modifies the structure of your body so as to make you healthier.
 

What is ageing?
 

• In biology it is said that function follows form, and in fact this is true of all machines. Machines do the things they do because of the way they are set up, because of their shape, because of their structure.
• Damage can be defined as any structural change that causes a loss of function.
• Any machine will do damage to itself in the course of normal operation.
• Ageing, then, is the process by which a machine loses function as a result of damage sustained from normal operation.
• The human body is a machine. Biological ageing is a progressive loss of function caused by damage that the body does to itself.
• Ageing is not a thing. There is no single process that is or causes ageing, it's just the body gradually breaking itself in many different ways.
   

For this reason, I don't actually use the word "ageing" very much internally - it seems confusing and unnecessary to me. If you damage a machine then by definition it won't work as well as it did, and if you damage it too much then it'll stop working altogether. Doesn't matter if the damage is caused by something external or by the machine itself. The word "ageing" makes this sound more mysterious than it is, like there's some separate magical phenomenon that causes organisms to slowly decay and die. Ageing is a mysterious answer to a mysterious question [LW · GW], and you could argue that it belongs in the same dustbin as phlogiston or elan vital.

I can grudgingly accept that we need a word for the general phenomenon by which people slowly decay and die with the passing of years, and ageing is that word. The problem is that it inclines us to imagine some single thing that causes decline. I'd accept "progressive loss of function due to intrinsic damage" as a reasonable definition of ageing, but only because it's clear about cause and effect. If you go looking for ageing as a cause of functional decline then you will search forever, because you're searching for something that doesn't exist. There is no single branch of biology, no mechanism, no clock, no organ, no system, no molecule, no separable component of any kind that is primarily responsible for ageing. The war on ageing encompasses all aspects of biology, because ageing is the simultaneous damage and decline of all biological systems.

Needless to say, if your machine is malfunctioning, then to make it work properly again you must fix it. Sounds so obvious that it's weird to even say it, right? And yet, when our bodies malfunction late in life, we mostly do not attempt to fix them. Instead, we try to treat the diseases themselves, almost like they were infectious diseases. We've been thinking by analogy, instead of from first principles. If we're ever to make serious progress against the chronic diseases of old age, we have to stop treating disease, and start fixing damage.

Stem cell therapy is prototypical damage repair. Stem cell therapy is cool, exciting and controversial because it modifies the body's structure directly - the damage repair paradigm simply extends this principle to all the other types of damage that fuck us up besides cell loss. Our oldest fields of medicine today (excepting surgery) are infectious disease and cancer. Cancer is very much like being infected by your own cells, so in both cases, we are fighting something other. But to defeat the pathologies of age, we must break the taboo against modifying old bodies to be more like young bodies, because the only difference between the bodies of old and young is that young bodies are healthier. Nobody really works on ageing, and nobody really works on longevity either - we work on health, of which longer life is but a side effect. There is no such thing as healthy ageing - psychological changes excepted, not one aspect of ageing is good for you. Biological ageing is loss of health.

What does it really mean to be healthy? What is health? My answer to that question is "the average 25 year old". Being healthy means having a license to abuse your body and not pay for it the next day. Healthy bodies are better at homeostasis; they can tolerate greater perturbations from their set points and return to those set points faster. Healthy bodies have redundancy, they are robust, they are set up to tolerate certain amounts of damage without loss of function. They can move faster, think faster and heal faster. They can take more abuse, and don't require careful management of sleep, diet and stress in order to function optimally. They rarely get sick. These are all things that we think of as "youth", because they correlate so strongly with low chronological age that they might as well be the same thing. But they're not.

Chronological age and ill health have progressed hand in hand for 100% of all humans who have ever lived. One consequence of this outrage is that age and sickness have become conflated in peoples' minds, as have youth and health. The fountain of youth does not literally make people younger, because it is not a time machine. It makes people healthier. Normally when we think “health” we think “lifestyle”, but in the long run, lifestyle is something we do to preserve health, not restore it. Being healthy does not mean having a healthy lifestyle, it means having a body that is functional and robust. It's about how big a hit you can take. Health is the absence of damage, ageing is the accumulation of damage, and rejuvenation is the reversal of damage, therefore healthcare without rejuvenation is grossly stunted. True healthcare is something we have never known. 

Confusion about what ageing is, coupled with the extension of frailty that recent decades have brought us, has led to a common misconception known as the Tithonus fallacy. Apparently, people think you're actually going to look and feel like you're 150 when you're 150. Hopefully the above paragraphs make it clear why this will not be the case: old people look and feel like shit because they are damaged and unhealthy, and this is the same thing that causes them to die. People don't die because they get old, they die because they get sick. Perhaps the term "longevity" is problematic, by implying that we're working specifically on making people live longer, as if we were going to cure all the diseases of ageing but leave ageing itself alone, condemning us to an indefinite future of frailty, tiredness and wrinklyness. But we're not going to cure the diseases directly - that's what we've been trying to do, and it hasn't worked, as I will explain later. The only way to cure those diseases and significantly extend lifespan is to repair the underlying damage that causes them, and that damage is the only difference between an 80 year old body and a 25 year old body. I doubt it would be possible to keep people alive in a state of frailty much longer than we currently do, because it's the frailty that kills them.
 

I don't know how long it will take for rejuvenated people to start looking like 25 year olds. What I do know is that "25 year old bodies" is what we will start to approach asymptotically, once rejuvenation becomes the dominant field of biomedical research and medical practice. The better we get at fixing damage, the younger people will look when they step out of the rejuvenation clinic; it will be a world in which you get slowly healthier over time instead of sicker.
 

What is damage?

I defined damage as "any structural change that causes a loss of function", and it's important to recognize that this is a very broad definition. The words "damage" and "structure" tend to conjure the image of scratches, dents, cracks, erosion, "wear-and-tear", disorder, loss of pattern. That's what damage looks like in man-made machines, but in biological machines it's quite different. A human is a machine made up of trillions of tiny robots called cells, each with a quasi-independent life of its own, which are constantly striving actively to maintain homeostasis. Arguably the biggest single difference between organisms and synthetic machines is that organisms are constantly repairing themselves.

This broad definition of damage can make it seem like I’m cheating somewhat. I’ve basically defined it in such a way that any change that makes people better when reverted automatically counts as damage. But this is precisely the strength of damage as a way of thinking: being defined counterfactually (damage is that which would improve function if it were repaired), it focuses the mind on what we can actually do that would make a difference. Identifying damage is the same thing as identifying therapeutic targets. To say that X caused Y is to say that Y would have gone differently if X were changed. Damage is thus defined as the root cause of pathology, as far upstream as it is possible to go without trespassing into the metabolic processes that cause damage. Judea Pearl would be proud. 
 

 

The taxonomy of damage shown above was proposed by Aubrey de Grey in 2001, and has become known as the SENS (Strategies for Engineered Negligible Senescence) approach to ageing. Importantly, it groups damage by the broad class of intervention required to fix it. Each damage type listed has many many sub-types within it, but they can all be fixed by similar means. If we can selectively destroy one type of slowly-accumulating bad cell then we can use similar means to destroy others; if we can discover enzymes that break down one type of intracellular junk and find a way to deliver those enzymes, then we can use the same approach on other types of junk.

Note also that 5 of the 7 damage types are all bad things that accumulate, such that "fixing" them simply means removing them. Reversing ageing can feel like an impossible task because we clearly lack the technology to manually put all the cells, molecules and atoms back in the right places as they become disarrayed, but the good news is that we don't have to: they're already really good at doing that themselves, so to a large extent we just need to remove the things that are stressing them out so they can do their jobs.

One of Aubrey's more controversial claims is that this taxonomy is comprehensive, that is, all the damage we need to periodically fix to stay biologically young and stave death off indefinitely falls into one of these categories and is amenable to therapy. Diving into that claim in detail would require a whole separate essay (Aubrey wrote a whole book about it), but I'll state my subjective assessment here. I have some niggling doubts about it, but I feel confident that it's comprehensive enough that intervening in all seven categories will yield some level of unmistakable rejuvenation and healthy lifespan extension. If we make it that far, then it's very unlikely that we'll just stop and give up if it turns out there's some other damage we need to fix, or if one of these categories turns out to be harder than we thought. As with all areas of technological development, the more we do it, the better we'll get at it.

The other reason I don't worry too much about the comprehensiveness of this taxonomy is that it's kind of beside the point. The point is that damage repair is a revolutionary new approach to medicine, which is something we always want regardless of whether it'll make us amortal or not. Few people believe it's even possible for medicine to keep humans alive indefinitely, but that doesn't stop us spending billions on Alzheimer's research. Damage repair is just a better way of doing what we're already trying to do. 

 

You can’t stop it, but you can reverse it

Intuition dictates that you’ve got to walk before you fly. If ageing is advancing upon us like the out of control cruise ship in the movie Speed 2: Cruise Control, then surely we first have to slow it down before we stop it, and stop it before we can reverse it.

Intuitions can be misleading.

All seven damage types in the SENS platform are direct, unavoidable by-products of ordinary metabolism. Their accumulation can sometimes be slowed by living a healthier lifestyle, but they are present and ever-growing in all of us. Halting their accumulation altogether would require a radical redesign of how the human body works, and that is a much harder task than merely reversing said changes once they’ve already happened. The former requires us to redesign the human body into some novel architecture that somehow does not damage itself over time - and of course, this is no good for people who are already damaged and suffering today. But the latter only requires us to re-engineer the body back to a youthful structure, which we already know functions very efficiently.
 

Source: Aubrey de Grey

Note: T-headed arrows mean “inhibits”

 

This is the reason why I don’t cite research into calorie restriction, metformin, rapamycin, resveratrol, sirtuins or longevity genes as reasons to get excited. These interventions, which you might term the  “gerontology” approach, all aim to modestly slow the ageing process, and the return on such investments, in terms of healthy years gained and suffering avoided, looks underwhelming to me. Not only that, but they sometimes feel a bit like voodoo, lacking a clear story as to how exactly such interventions should be expected to preserve function. Damage repair therapies aim to directly reverse changes that clearly cause problems, whereas gerontology mostly targets things that are merely associated with age-related decline. For example, “longer lived animals express more sirtuins, let’s try supplementing humans with sirtuins and see what happens”.

Another problem with the gerontology approach is that assessing its efficacy is really difficult. Since damage repair aims to rapidly reverse the accumulation of damage, you can expect to observe the removal of damage, improvement of ageing biomarkers (more on these later), and hopefully some gain of function shortly after the therapy is administered, if it works. Gerontology, on the other hand, only aims to moderately slow the progress of ageing, so no matter how you measure that progress, it’s going to be years before you can confirm that effect in humans.

Indeed, this is part of the reason why most evidence for gerontology approaches is in mice. Calorie restriction can extend lifespan by up to 40% in mice, which is easy to measure since they only live about 2 years naturally. Unfortunately, it seems unlikely that any such approach could yield a comparable proportionate life extension in humans. We would have discovered a very long time ago if starvation could extend human lifespan by 40%, and there is little reason to believe that drugs that trick the body into thinking it’s being starved could do much better (resveratrol, metformin, rapamycin).

Calorie restriction is definitely good for you, as are exercise and sleep, and by all means, experiment with supplements to optimise your own health as much as possible. Even if it only extends your life by a couple of years, that might be the difference between living long enough to live forever and dying just before genuine rejuvenation therapies arrive. But in the long run, slowing the ageing process is only kicking the can down the road, and it is only rejuvenation, synonymous with the reversal of damage, that can truly rescue us from ageing. Gerontology is neither rejuvenation nor a stepping stone towards it, despite its humbler aspirations. Rejuvenation is harder, but it is doable, and the return on investment will be immeasurably higher.

 

Stop treating disease, start fixing damage

Our current paradigm for treating age related disease generally revolves around finding a single small molecule, that binds to a single target, inhibiting a single pathway, to treat a single disease. It's like we see disease as a state in which the body is doing something bad, so we try to treat disease by stopping the body from doing what it's doing. That modern healthcare has earned the moniker "sickcare" gives you some idea of how effective this has been. 

Previously I had accepted that our mediocre results against chronic illness were reflective of the overwhelming complexity of biology, that biomedicine was just a ridiculously hard problem, and our best chance was to keep pouring billions into the pharmaceutical industry while hoping that advances in AI would make the complexity tractable. When viewed through a damage repair lens however, it suddenly seems a lot more obvious that this whole approach is doomed no matter what resources we throw at it. 

Function follows form; these things we call diseases are functional consequences of damage, and if you don't repair that damage then it will continue to accumulate, faster and faster as damage causes more damage, including to the body's own damage repair systems, and eventually the damage overwhelms you no matter what else you do. Even if you succeed in mitigating the effects of current damage, it will just accumulate further until it causes yet more problems that you can't mitigate.

Not only that, but the whole concept of "disease" is somewhat arbitrary. What exactly is a disease anyway? Sometimes it's unclear to me whether disease refers to a set of symptoms or a cause of symptoms. Wikipedia defines disease as "a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury". The word "condition" is vague, and could refer to cause or symptoms, likewise, degraded structure means cause while degraded function means symptoms. Furthermore, the pathologies of age don't always fall neatly into distinct buckets; often there's a continuum of dysfunction with no clear boundary between one disease and the next. Anyone who's presented symptoms that a doctor struggles to classify knows what I'm talking about - sometimes there simply is no diagnosis that cleanly captures a patient's symptoms.

With infectious diseases, there is a mostly one-to-many mapping between pathogens and the symptoms they cause. Thinking in terms of disease makes sense when dealing with infection: a guy has a particular kind of cough, it's caused by this particular pathogen, and we can kill it with this particular antibiotic. The disease name can refer to both the symptoms and the pathogen together, since they go hand in hand. Indeed, I find it telling that Wikipedia's Disease page leads with a picture of some Mycobacterium tuberculosis. I think our usage of the word "disease" in relation to chronic illnesses is a holdover from our approach to infectious disease. We're good at treating infectious diseases, and instinctively we've applied the same thinking to chronic illnesses, but it hasn't worked. It's worked so badly that age related sickness continues to kill literally everyone who doesn't die of something else first.

One reason it doesn't work is that the relation between causes and symptoms is much more complex in the case of ageing than with infectious disease. Infections generally occur separately, and the causative pathogens are usually easy to identify from symptoms and verify by testing. When we say we've diagnosed an infectious disease, we mean we've identified the pathogen that caused the symptoms, and thus the treatment is known. Age related diseases on the other hand are typically more like syndromes, collections of symptoms whose root cause is poorly understood. This is because unlike infectious diseases, age related diseases have multiple causes which occur all at once, each of them causing multiple downstream problems which interact with each other in complex ways. The relationship between causes and symptoms is therefore many-to-many rather than one-to-many, with each damage type ultimately contributing to multiple overlapping downstream pathologies, so there isn't always a single type of damage that drives a particular illness. This is even more true when you consider that damage types can cause each other, whilst also damaging the systems that would normally repair them - this is why health declines exponentially in old age. In short, the chains of causality linking damage to pathology are long and tangled, that's why isolating a pathology is rarely useful with regards to treatment.

By contrast, focusing on damage rather than pathology bypasses this complexity by recognising that we don't need to unravel the mechanisms by which damage causes pathology, nor the mechanisms by which damage is created in the first place. We know that all age-related pathology is ultimately caused by some kind of damage, and we have a pretty good idea of the form and nature of that damage - indeed, we haven't discovered a whole new type of age-related damage since the 1980s, which strongly suggests that our current catalogue is comprehensive. 

If, in the course of debugging your code, you find something that is obviously a mistake, then it is wise to fix it immediately, whether or not you understand how that bug might be causing your program to misbehave. Personally, I do like to spend time picking those mechanisms apart until I understand them entirely, and I think that's good practice for engineers who are building systems. But in biology, we are not building our own system, so we do not have the option of keeping it well documented and well understood. Instead, we are presented with an ungodly mess of uncommented spaghetti code, an enormously complex system that we did not ourselves design, but must still debug.

Another problem with thinking in terms of disease is that we generally don't consider our symptoms to be a disease until they reach some arbitrary threshold of pain and dysfunction at which they seriously interfere with our lives. Think of all those sub-clinical aches and pains that you're probably growing accustomed to if you're above the age of 30. These pains are as much a manifestation of ageing as is Alzheimer's disease, and just like Alzheimer's, they must be caused by some form of damage. Why else does your neck hurt when you're 45 but not when you're 25? Something in your body must have changed to have caused that, and the solution is to revert that change. Why wait until you can no longer sleep before getting it fixed? Probably because most of our current treatments have such unfavorable risk/benefit ratios that it's hardly worth trying them until you are quite desperate.

This brings me to another massive advantage of damage repair over disease treatment. Directly modifying the body's structure like a mechanic fixing a car may sound dangerously gung-ho, since we clearly don't understand the system we're meddling with. It may sound like it would be safer to only interfere with processes whose immediate role in disease is well understood, but it's actually the other way round. Most modern pharmaceutical products work by inhibiting the function of some receptor, signalling molecule, enzyme, gene or biochemical pathway, usually for the long term (since, you know, it won't actually cure you - that's why they're called chronic illnesses). The problem is, we're supposed to have those things. Whatever biomolecule you target will generally have at least one important role somewhere else in the body, probably more like 50 roles since this is biology. Damage, on the other hand, is defined in such a way that it's definitely not supposed to be there. You're not supposed to have senescent cells everywhere, your lysosomes are not supposed to be clogged with lipofuscin, your proteins are not supposed to be gummed together by advanced glycation end products, we know this because a) we can clearly see how these things impair function and b) they are absent in healthy youthful bodies that work correctly. 

The damage repair therapies themselves may put transient stress on the body (e.g. cellular debris from the destruction of senescent cells may cause inflammation until it is cleared up by macrophages), and we may screw up and produce off-target effects (e.g. killing innocent cells, accidental interactions with non-target molecules). But the point is that we don't have to worry about side-effects from on-target effects. Not only that, but most repair therapies under consideration today remove whole chunks of damage all at once, and it takes decades for damage to re-accumulate, meaning repair therapies can be applied in a "hit-and-run" fashion rather than constantly. This is intrinsically much safer.

Instead of trying and failing to treat age-related diseases one by one, we can slow, prevent and alleviate one or more age-related syndromes at once by intervening in fundamental ageing processes^[1]. This way of thinking has acquired a name: the Geroscience Hypothesis^[2][3]. It's a little broader than the damage repair framework since it includes slowing the accumulation of damage as well as repairing it, but the idea that the best way to cure age-related disease is by intervening further upstream in ageing itself is spot on.

It would be very nice if the FDA could be made to understand all this. Right now, nearly all longevity trials are required to have some specific disease as their primary endpoint, even though the interventions they're testing often improve health and resiliency generally. 

To progress more rapidly, we need to be allowed to evaluate and ultimately prescribe drugs specifically for the purpose of repairing damage. The alternative is to allow stuff that is unambiguously bad for you to progress and accumulate, refusing to remove it until it causes symptoms, which you may struggle to connect to that damage. Although it goes without saying that doctors must weigh the benefits of treatment against the risks (which are intrinsically high for novel treatments), allowing damage to progress risks causing secondary damage that we might not know how to fix, or even know exists.

There is some sign of movement on this front: a recently funded trial to test the lifespan boosting effects of the anti-diabetic drug metformin has created a new FDA-approved endpoint that represents ageing in all but name^[4]. Instead of measuring the severity of some particular disease, it's a composite metric tracking multiple biomarkers of general function. The hope is that once this trial progresses, other companies will feel confident using the same endpoint for their own products.

 

Primary damage, secondary damage

I've defined damage as "any structural change that causes a loss of function", with causality understood in the Judea Pearl sense of "that which would make a difference if we were to change it". But ageing bodies show changes in just about all aspects of structure, so how do we know which are causative, in the sense that reversing them would cause function to improve? We could of course proceed empirically, targeting different structural alterations in turn to discover which ones have an impact on function. But that leaves us with a lot of targets to work through.

My understanding is that the SENS platform cuts this workload down by emphasising primary damage as the rational target for intervention. Primary damage is that which is created as a direct side-effect of ordinary metabolism. This is a matter of identifying the root causes of disease - which is arguably what medical science is all about. Age-related diseases are caused by age-related structural changes, and although age-related structural changes cause each other in complex networks, they can all ultimately be traced back to ordinary metabolic processes - that's why these changes eventually affect everybody, regardless of lifestyle. By targeting primary damage, we trace the etiology of disease as far upstream as possible without trespassing into metabolism.

Atheromatous plaques, macular edema, stooped posture and cell membrane stiffening are all examples of secondary damage that exist downstream of the primary damage listed in the SENS platform. Fixing the SENS damage types should prevent them from occurring, but won't necessarily fix them if they're already there. Some of them might fix themselves once the primary damage is fixed, others might require separate interventions in those individuals old enough to have already acquired them before we can fix the primary damage that causes them.
 

AGI, Nanotechnology

We do not need to wait for AGI nor molecular nanotechnology to solve this problem for us. I may be wrong here, but I get the impression that people in the transhumanist/rationalist space sometimes have the mindset that ageing is such an intractable problem that it isn't even worth trying to unravel it with our pitiful human meat-brains, to the point where it would be easier to just invent God first and then get God to do it for us. The problem is that a) we don't know how to do that and b) it'd be super dangerous if we did, but we do now have plausible plans for repairing damage.

I liken it to SpaceX's plans for Mars colonisation: we don't need any major scientific breakthroughs to make it happen, we just need to overcome a lot of engineering problems, and humans are good at those. Elon isn't betting on miniaturised fusion power or aerospike nozzles or esoteric ultra-high-performance materials, he thinks we can get to Mars using relatively conventional technology, and there's no obvious reason why his plan shouldn't work. I think that's where we are with ageing right now. We know that all loss of function is caused by damage of some kind, we know what are the main types of structural decay that drive ageing, we haven't discovered a totally new one since the 1980s, and there exist plausible strategies for the elimination or obviation of all of them.

As for molecular nanotech, I will note that a) manipulating matter at the atomic scale in a foundry is not the same as manipulating atoms in the body, and b) we already have nanobots, they're called cells. The biotech sector is the real life nanotech sector. Cells are pre-existing nanobots, and they’re already perfectly adapted for getting shit done inside a living body. Sure, somewhere in design space there must exist nanobots that could do a more effective job of building and maintaining the body than cells do, but even with perfect nano-scale manufacturing tech, the difficulty of designing nanobots to do what cells do would be enormous. We should just use the cells.

 

Why do we age?

Wrong question. Ageing is primarily a phenomenon of physics; all machines do damage to themselves, so the real question is why do we live as long as we do, and why are there some species that don't appear to age at all? The answer is that evolution has equipped us with damage repair systems of our own, and these keep us alive far longer than we would survive for otherwise. 

An example: ordinary metabolism produces lots of waste products, and the body has to break them down or eliminate them or else they'll build up until they kill you. For lysosomal storage disease patients, whose waste degrading enzymes are broken by a mutation, that's exactly what happens, and they tend to die young. 

The reason humans didn't evolve to live even longer than we do is that life in the ancestral environment was rough, and so a mutation that extended health into later life would have no actual effect on most people, since they'd generally starve, freeze, die of infection or be killed before the age of 40 anyway. And if that mutation cost even a little bit of extra energy to run the damage repair machinery during youth, then it could confer negative fitness and be actively selected against.

 

Ageing Clocks

Ageing clocks are a rapidly growing field aiming to quantify ageing, so that we can quickly assess how effective an intervention has been at reversing or postponing it. It's long term outcomes that we ultimately care about (how long before the patient gets sick, how long before they die), but we have to do a lot of waiting to measure those things directly, and time is of the essence. Ageing clocks allow us to predict those outcomes from biomarkers that we can measure shortly after treatment. The approach was pioneered by Steve Horvath^[5], who built a regression model that predicts chronological age from DNA methylation state. This prediction is what the term "epigenetic age" refers to. Predictions of chronological age from biomarkers more generally are called "biological age". If a person's biological age is significantly lower than their chronological age then we can say that they've "aged well", although "aged more slowly" would be more accurate. It's not fundamentally different to guessing a person's age by looking at their face, and using that as a proxy for their overall health - the difference is that we're using molecular biomarkers as input instead of faces, and it's done by a machine, so it's consistent.

This approach is perfectly valid, because chronological age correlates so well overall damage levels and remaining healthspan in today's world that they both make excellent surrogates of each other, so predicting chronological age pretty much means predicting damage levels and remaining life. Saying "he looks like a 30 year old" is the same as saying "he looks pretty healthy". Health is the absence of damage and ageing is the accumulation of damage, so estimating greater age means estimating greater damage and lower health. I do feel the term "ageing clock" is a little misleading, though. It implies that there's a single hidden process that drives and orchestrates the functional decline we call ageing, that the body holds within it a secret number called "biological age" which ticks up regularly, that we can read it with a regression model, and perhaps that we could even edit this one thing directly, and thus sidestep all the divide-and-conquer damage repair stuff by just telling the body to be younger. Maybe I'm reading into it too much. To be abundantly clear, I'm not saying that ageing clocks themselves are bad - it's super important that we have a way to measure how healthy people's bodies are. I just think they're badly named.

More recent ageing clocks such as GrimAge^[6] have been trained to estimate remaining healthspan directly, rather than using chronological age as a surrogate. This may prove to be more useful. The worry with training to estimate age rather than healthspan is that there may be "superficial" biomarkers, which reliably change with age but cannot be said to cause ageing, in the sense that reverting them does not restore function because they were mere side-effects of whatever it is that really does matter. An age regression model would learn to use these markers, and would thus predict lower biological age after a therapy that reverted them, even though they don't really predict a better outcome. A model trained explicitly to predict the things we actually care about would presumably be less susceptible to such a failure mode.

 

Examples

This essay focuses on conceptual shifts, but I need to emphasize that this is not just a cool way of thinking - these ideas are being put into practice in laboratories right now, and they are yielding results. Here I describe four damage repair therapies currently in development, which illustrate the principles outlined above.

 

Senolytics

Senescent cells are a type of bad cell that accumulates with age. Often referred to as "zombie cells", they have lost the ability to divide, but that's not what makes them actively dangerous. Senescent cells are relevant to ageing because a significant fraction of them produce senescence associated secretory phenotype (SASP), a witch's brew of inflammatory cytokines, proteolytic enzymes, fucked up lipids and growth factors^[7]. SASP plays a key role in driving inflammageing, the systemic, chronic, sterile inflammation that develops slowly with age and is widely understood to be bad for you^[8]. Senescent cells accumulate at the pathologic sites of many age-related disorders including osteoarthritis, atherosclerosis, Alzheimer's and macular degeneration, and bad things seem to happen to mice when we inject them with more of them. SASP can also cause other cells to become senescent, which partly explains how their numbers increase exponentially in old age. So we have these broken cells who proliferate in the elderly and look like they're causing trouble: sounds like a great example of an age-related structural change that causes a loss of function, i.e. damage.

Cellular senescence probably evolved primarily as an anti-cancer mechanism. Cells can become senescent in response to a wide variety of stressors^[9], particularly those which involve DNA damage, suggesting that senescence preserves function by preventing the replication of damaged DNA. The prototypical form of cellular senescence is replicative senescence, discovered by Leonard Hayflick in 1961^[10], in which cells cease to divide after a certain number of generations due to the depletion of telomeres (little end-caps on chromosomes). Every time a cell divides, the daughter cells will have shorter telomeres; when they run out, the ends of chromosomes start to fuse and the cell becomes senescent. The Hayflick Limit, as it has become known, can be thought of as a last line of defense against cancer, kind of like a recursion depth limit: any would-be tumour that does not figure out a way to lengthen its telomeres will inevitably hit the Hayflick limit, become senescent and cease to grow, leaving you with a mole or skin tag instead of a tumour.

Preventing cells from becoming senescent, or reversing their senescent state, may therefore be a bad idea, but what we can do is remove them. Since they are relatively few in number, killing them and allowing them to be replaced by the division of healthy cells is a perfectly viable strategy for repairing the damage that they constitute. Fortunately this turns out to be surprisingly easy, with several repurposed FDA-approved anti-cancer drugs showing senolytic action. Progress in developing senolytic therapies has therefore been gratifyingly rapid, with several clinical trials currently in progress. Given that SASP was only discovered in 2008^[11], this is remarkably fast by typical drug discovery standards. Senolytic drugs are therefore arguably the tip of the spear in the quest for bona-fide rejuvenation therapies.

These clinical trials are very well motivated by studies in rodents. Senolytic drugs have been found to restore cognitive ability by improving neurovascular function^[12] and reducing brain inflammation^[13], alleviate obesity-induced anxiety^[14], restore muscle hypertrophy^[15], and extend median lifespan^[16]. A first-in-human trial of the first senolytic therapy, dasatinib + quercetin, significantly improved physical function in idiopathic pulmonary fibrosis patients while being well tolerated^[17], and a later trial confirmed that it reduced markers of cellular senescence in diabetic kidney disease patients^[18]. Senolytic therapies are also being pursued by multiple private companies, notably Unity Biotechnology and Oisin Biotechnologies.

One theme that emerges from this body of work is that rather than being cleanly associated with certain diseases, senescent cells are broad-spectrum disruptors of health generally, contributing to many if not most age-related chronic diseases along with more nebulous afflictions such as frailty and loss of gait speed^[3]. Hickson et al.: "If senolytic agents can be shown to be effective for several individual age-related conditions, they may prove to have a role beyond alleviating single diseases: they may be effective in reducing the multimorbidity common in elderly patients"^[18]. Stop treating disease, start fixing damage.

 

LysoClear

Age-related macular degeneration (AMD) is a leading cause of central blindness among the elderly population worldwide^[19]. It is caused by an accumulation of intra-cellular waste, notably a substance called A2E, which is produced as a by-product of the high-energy photochemistry which transduces incoming photons into neural impulses in retinal rod and cone cells. Humans do not possess enzymes capable of degrading A2E, so it ends up slowly accumulating in pigmented retinal endothelial (RPE) cells, which form the posterior lining of the retina. The dose makes the poison, and so at some point, A2E reaches sufficient concentration that it begins to kill RPE cells, which is unfortunate because RPE cells are essential for the survival of rods and cones. The result is a progressive loss of central vision, right where the density of rods and cones is greatest. 

Standard of care for AMD consists of vitamin supplements^[20]. These can moderately slow the progress of AMD, but they cannot stop it, nor reverse it. In the more advanced and serious "wet" form of AMD, in which new capillaries grow into the retina, leak plasma and cause macular edema leading to legal blindness, we prescribe VEGF (vascular endothelial growth factor) inhibitors. VEGF inhibitors are very effective at preventing catastrophic vision loss and even restoring some function in wet AMD, but they are not without side-effects^[21]. VEGF is an important signalling molecule that we are supposed to have, which plays a multitude of roles throughout the body, so it's not surprising that knocking it out has its risks. 

It's well established that A2E plays a causative role in AMD, it's definitely not good for you, and young people don't have a lot of it. What if instead of trying to inhibit AMD's pathological processes with supplements and angiogenesis inhibitors, we targeted the root cause of AMD by removing A2E from the body directly? I don't mean to imply that prior researchers had been stupid here; humans don't come equipped with enzymes capable of degrading A2E so it wasn't exactly obvious how to get rid of it. It took the pioneering work of the SENS Research Foundation to discover a bacterial enzyme that could do the job through something akin to bioremediation; this work was later spun out into LysoClear and pursued by Ichor Life Sciences. LysoClear is currently undergoing pre-clinical trials in vivo^[22], and has produced encouraging results so far^[23].

 

Thymus Regrowth 

The thymus is a small lymphatic organ located behind the breastbone. It is the site at which T-cells mature (hence the name), and where they undergo a filtering process that kills T-cells that see host proteins as foreign or that respond to "naked" antigens, which are not presented by other immune cells. The thymus is an unusual organ in that it recedes (or "involutes") early in life, beginning at infancy and having become mostly replaced by fat tissue by adulthood. Without the thymus, the body is unable to produce new naive T-cells, and this is thought to play a role in both the decline in resistance to infection and the rise in carcinogenesis with age^[24]. Why would such a loss of function evolve? It may be an example of antagonistic pleiotropy, by which an organism may trade long-term self-maintenance for short-term survivability. Thymic T-cell production is energy intensive, and the T-cells produced early in life seem to last pretty well until old age, so it has been suggested that thymic involution may enhance reproductive fitness early in life, while its cost is not borne until late life, by which time most people in the ancestral environment were dead anyway^[25]. 

Greg Fahy is the pioneer of vitrification for organ and tissue cryopreservation (which naturally is also state-of-the-art for whole body cryopreservation in cryonics). These days, he works on regrowing the thymus. Turns out this is way easier than you'd think - you don't need stem cells or bioprinting, it can be done to an impressive degree just with small molecules, namely with a combination of human growth hormone, DHEA and metformin^[26]. The hGH makes the thymus regrow, and DHEA and metformin are diabetes medications that counteract the excessive insulin production caused by hGH. The original trial was quite small, so an extended and improved re-run is currently in progress, which so far is replicating the original results^[27]. 

This particular example is still very preliminary, but I find it compelling because this one intervention appears to reverse multiple age-related changes in humans, not all of which are obviously related to immune function. Improvements measured by Fahy's team include not only confirmed regrowth of the thymus and bolstering of naive T-cell populations, but also a reduction in cancer risk factors and systemic inflammatory markers, improved kidney filtration rate, and improved prostate health. Also a guy's hair apparently grew darker again. This probably isn't entirely due to thymic regrowth, since hGH, DHEA and metformin are all known to have anti-ageing properties of their own, and there's certainly some synergy between them. 

It also illustrates that “damage” does not necessarily mean “wear-and-tear” - thymic involution in particular appears to be very much a regulated change and a part of the developmental program. But damage is defined here as any structural change that causes a loss of function, regardless of how it came to be. It doesn’t ultimately matter how the thymus involutes nor why, in the proximal or evolutionary sense - we just want our T-cells back.  

Another significant outcome from hGH + DHEA + metformin is the first-in-human reversal of epigenetic age, according to four different ageing clocks^[26]. Patients' epigenetic ages were on average 1.5 years younger at the end of treatment, which lasted for one year, than they were at the start, meaning their biological age was 2.5 years younger at the end of treatment than it would have been naturally. This is important because epigenetic clocks are standardised, so they don't allow the authors to cherry-pick markers that tell a positive story. This is strong evidence of a broad-spectrum rejuvenation effect - exactly what you would expect when you fix a key system that's obviously broken.
 

Source: Reversal of epigenetic aging and immunosenescent trends in humans 

 

Curing Atherosclerosis

Cardiovascular disease, driven principally by atherosclerosis, is the leading cause of death globally^[28]. Briefly: cholesterol gets stuck in your artery walls, macrophages come to clean it up, it poisons them and they die, more macrophages come to eat the dead macrophages and they die too, and after several decades of this you end up with an atheromatous plaque: a grossly visible accumulation of dead macrophages and pools of extra-cellular cholesterol. Eventually the plaque ruptures, spewing debris into your arteries, blocking them and causing you to die. This process begins in youth, and will eventually kill everyone who doesn't die of something else first, regardless of lifestyle. 

The state-of-the-art treatment for cardiovascular disease is statins, which moderately slow the growth of atheromatous plaques by reducing the amount of cholesterol-carrying LDL exported by the liver. Statins have side effects that make them unusable by some patients, for which reason they are rarely prescribed until a plaque has been confirmed, by which point its progression is typically quite advanced, and they do nothing to reverse the growth of that plaque. Can damage repair do better? Instead of slowing the plaque's growth or learning to live with it, can we remove it directly? Here there are not one but two commercial enterprises pursuing promising damage repair approaches: Repair Biotechnologies (founded by Reason, the guy from fightaging.org), and Cyclarity Therapeutics. 

Repair are developing a cell therapy consisting of macrophages enhanced with their proprietary Cholesterol Degrading Platform (CDP). CDP enabled cells are able to degrade seemingly limitless amounts of cholesterol internally, and so do not succumb when doused with the stuff. Furthermore, these macrophages are derived from allogeneic "off-the-shelf" stem cells that have had their immune markers stripped from them - this makes the whole process considerably cheaper and more streamlined than extracting, modifying and re-injecting the patient's own macrophages.

Source: Repair Biotechnologies

 

Armed with upgraded cholesterol processing ability, CDP-enabled macrophages are able to do the job that regular macrophages fail so catastrophically at: inject them into a mouse with atherosclerosis and they dive into the plaque and eat it, shrinking its size substantially as they break the cholesterol down into harmless metabolites. 

Meanwhile, Cyclarity (formerly Underdog Pharmaceuticals) are pursuing a small molecule approach that removes 7-keto-cholesterol (7KC) from cell membranes. 7KC is a form of oxidized cholesterol produced by reaction with an oxygen radical. Unlike regular cholesterol it is straight up toxic and has no known physiological function, but it does play a role in many age related diseases, not just atherosclerosis^[29]. It's a great example of a single type of damage that plays a role in many age-related disorders (check the review article I cite, it's really a lot). Like A2E, 7KC is a toxic byproduct of normal metabolism that accumulates slowly enough that most humans in the ancestral environment were already dead before it became a problem, therefore evolution never got around to clearing it up. If cholesterol is bad for macrophages in excess, 7KC is just bad full stop.

Cyclodextrins are soluble, macrocyclic carbohydrates that can thread themselves around a small hydrophobic molecule like cholesterol and bind to it, then float off into solution with it. Cyclarity's approach uses rationally designed cyclodextrins with high affinity and specificity for 7KC to remove it from cell membranes^[30][31]. They are non-toxic and are excreted from the body via the kidneys, which is ultimately how they remove 7KC from the body.

 

Combination Therapy

Damage repair therapies have so far elicited only modest lifespan extension in mice. It's impressive, but if it's such a great idea then why hasn't it yielded serious lifespan extension yet?

The problem is that damage takes many different forms, and any one of them can kill you if it gets bad enough. Not only that, but they accumulate at such a rate that they'll all kill you at around about the same age. How could such a coincidence occur? Recall that long lived species like ourselves live long because they have evolved to repair damage. But there's no point in repairing different types of damage at different rates (that is, such that they become problematic at different ages). If you do that, then your lifespan will be limited by whichever type of damage kills you first, and your stronger ability to repair all the other types will be wasted. In this situation, there is no selection pressure to maintain the repair capacity of any except the fastest accumulating damage type, because mutants who repair other damage types more slowly will live no shorter lives. If damage type X kills an organism at 20 years of age but damage type Y would only be a problem if it lived to 50, then a mutant who repairs Y more slowly, such that it becomes lethal at 40, would still die at 20 due to X. Without selection pressure to maintain them, random mutations will degrade excessively efficient repair systems until all forms of damage become relevant at the same age. And if you save energy or nutrients by repairing Y more slowly, then that’s a fitness increase and will be actively selected for.

With this in mind, it is not surprising that senolytics cause only modest lifespan extension in mice. It's surprising that they are able to extend lifespan at all. The fact that they do, probably implies that senescent cells have a deleterious effect on the repair of several other forms of damage, such that they all accumulate a little bit slower when senescent cells are cleared. But the real extension of healthspan will come when we repair multiple forms of damage at once.

 

Epigenetic reprogramming 

In 2006, Shinya Yamanaka’s lab discovered that a group of four transcription factors known as OSKM (oct-4, sox2, klf-4 and c-myc) are sufficient to transform ordinary somatic cells into induced pluripotent stem cells (iPSCs). PSCs are able to proliferate indefinitely without hitting the Hayflick limit (they express telomerase, which lengthens their telomeres) and can differentiate into any somatic cell type, so naturally they’re pretty relevant to regenerative medicine. Since cells generally become more differentiated and less stem-like as an organism develops, transforming adult somatic cells back into iPSCs could be thought of as a reversal of developmental age.

As I understand it, the usefulness of epigenetic reprogramming is twofold: it can reverse the accumulation of epigenetic noise which has been proposed as a key driver of ageing^[32], and it can effectively create new stem cells in the body, which is potentially more elegant and easier to implement than injecting stem cells. 

The concept of regeneration has been perhaps conspicuously absent in this post so far, but here is a good place to mention it. You may know that there are some animals such as salamanders, hydra, and planarian flatworms, who are capable of regenerating whole limbs and other complex structures including brains following injury or amputation. Turns out mammals can do this too, but the ability becomes incrementally suppressed following the embryonic fetal transition (EFT, about 8 weeks post fertilization in humans)^[33]. Prior to the EFT, you can grossly mutilate an embryo (at least a mouse embryo, I don’t think it’s been done with humans) and it will regrow the lost tissue perfectly with no scarring.  

This is clearly a very important form of innate damage repair, since we have little idea how to manually reconstruct lost or damaged tissues. Organ bio-printing is a thing, but the masters of tissue assemblage and repair are cells themselves - it is their art that we imitate with bio-printing, and we can expect superior results if we can coax them into doing the job for us. Adult mammals of course can already heal from wounds, which is a form of regeneration, but it’s limited, it involves scarring, and they cannot regrow limbs or organs that are amputated. But if we get reprogramming right, we could potentially heal from greater harms - for example, application of OSK has been shown to regenerate crushed optic nerves in mice^[34]. 

The suppression of regeneration post-EFT probably evolved as an anti-cancer mechanism (although this view is disputed), since stem cells are cancer-like in many ways: both can replicate indefinitely, both show a metabolic shift toward aerobic glycolysis, and they both express similar genes that are suppressed in normal adult somatic cells. As such, we need to be careful when reverting cells to this state via partial reprogramming, and indeed it’s been found that if you rewind the developmental clock too far, cancer happens^[35]. 

Epigenetic reprogramming seemed to me like a competing approach to damage repair for a while, but now I just see it as a type of damage repair. In terms of the SENS platform, it’s an alternative approach to stem cell therapy for fixing cell loss, since it can enable cells to proliferate free from telomeric restriction in order to repair and replenish damaged tissues - kind of like creating stem cells inside the body. It may also turn out that random changes to the epigenome itself constitute an 8th category of damage in their own right - the questions are a) how much does it impact function, and b) how much might it normalise itself if we fix all the other things that stress cells out? We’ll probably have to find out empirically: try many combinations of damage repair therapies including epigenetic reprogramming to find the minimal, safest combination that yields the greatest improvement in function.

What is clear is that partial epigenetic reprogramming won’t be enough on its own. There are too many other things going catastrophically wrong in the ageing body for me to believe that reprogramming could fix everything. What about all the junk accumulating because we lack the genes to code for enzymes that can break it down? Epigenetic change cannot make a cell express genes it doesn’t have, so we’ll have to deliver either the enzymes or genes for the enzymes. How will reprogramming reduce atheromatous plaques, how will it remove advanced glycation end-products, how will it regrow the thymus? SENS Research Foundation have a piece here making the same argument in much greater detail. 

The results that excite me the most in reprogramming are regeneration-focused papers like this one, in which the optic nerves of mice were crushed and then regenerated by application of OSK (although the effects were diminished in older mice). One might argue that the SENS platform somewhat sweeps that kind of damage under the rug of “cell loss”, which to me seems like too limited a description. It’s not just the number of cells that must be restored, but the way they are organised relative to each other spatially; the magic of stem cells is not just that they replace lost cells, but that they know where to go, what to do and how to form functional networks once they’re there. It’s morphology that we’re restoring, not just numbers, and that requires us to invoke the magic of regeneration because we have no idea at all how to do something like manually repairing a crushed optic nerve at the cellular level. 

The results from most other reprogramming studies don’t seem super exciting so far^[36]. I see a lot of papers reporting reprogrammed cells that "look more youthful" in terms of their epigenetic, transcriptional and secretory profiles, but fewer that claim to restore actual function. Mouse lifespan has been marginally extended, but so far only in progeroid mice. A frequently reported endpoint seems to be reversal of epigenetic age, which is not super surprising given that the intervention is twisting the hands of the epigenetic clock directly. Epigenetic changes correlate with age (hence epigenetic clocks), but that doesn’t mean they’re a cause of ageing - cells may well be switching genes off and on as they adapt to the increasingly stressful environment they’re in due to other age-related changes. In that case, epigenetic reprogramming would be a bit like preventing rain by twisting the needle on a barometer - and then citing the barometer as evidence of weather control. This is consistent with the fact that thymic regrowth reduces epigenetic age without direct epigenetic reprogramming, and also with the fact that many studies showing reprogrammed cells acting more youthful are in vitro, meaning they’ve been taken out of the inflammatory environment of an aged body.

Regeneration is still quite mysterious (or rather, our understanding of it sucks [LW · GW]), therefore regenerative medicine still feels a bit like voodoo. Much of reprogramming so far seems to boil down to dosing mice with different reprogramming factors with different time schedules and hoping for the best. In contrast, the SENS platform emphasises combination therapies that remove things that are definitely not meant to be there and are almost certainly harmful. I get more excited about the various SENS branches because they have simpler and more direct rationales as to why they should improve function. Call me short-termist, but I get more excited by things that we can do right now and expect results. 
 

Morbidity compression

The widespread belief that the diseases of ageing and ageing itself are separate things has led to the idea that people will "die healthy" in their old age, once the cruel and debilitating diseases of ageing have been cured. Ageing itself, it is thought, is a benign and gentle killer, waiting to whisk us away one night once our allotted time on Earth is up. Bullshit, says I. People don't die because they get old, they die because they get sick. The boundaries between ageing and age-related disease are arbitrary; it is not possible to cleanly separate them, nor is it possible to cure age-related diseases without reversing the accumulation of damage, i.e. rejuvenating people. We have a choice: either rejuvenate, or make our peace with Alzheimer's disease, macular degeneration, strokes, cancer, cardiovascular disease, osteoarthritis, and all the other diseases of age that we currently spend billions fighting every year.

The easiest way to achieve morbidity compression would be to pursue total rejuvenation through damage repair as outlined above, live your life as fully as possible in a state of perfect health for 500 years, and then die by hitting a tree while skiing down everest. Alternatively, if 500 years sounds too long, we could implant all rejuvenation patients with a device that stops their hearts at some random time around the age of 80. If dying healthy at age 80 is what society truly desires, then I'm sure it will have no problem implementing this solution.
 

Longevity Escape Velocity

A note about longevity escape velocity (LEV) is appropriate at this point. The idea is basically that early rejuvenation therapies will buy you time in which the therapies can be improved further, thus allowing you to extend your deadline even further by the time that deadline arrives, and so on and so on. Not only that, but the deadline extends by a greater amount with each incremental improvement, because each time there will be fewer and fewer types of damage that we don't know how to control. LEV, then, is the rate of technological progress that, on average, extends your remaining life expectancy by more than one year per year. The upshot of this is that age-related mortality will become a thing of the past long before we are able repair damage comprehensively.

I find it a somewhat slippery concept to define precisely, but it boils down to this: people will stop dying of ageing before we have the technology to comprehensively rejuvenate them, because partial rejuvenation buys time in which to improve the tech further. LEV is the point at which people no longer die of ageing, and it comes before the arrival of comprehensive damage repair.
 

 

I said before that there are types of damage, each of which can kill you all by itself at around about the same age. However, within these types there are generally subtypes, which have an additive effect on the impairment of function. For example, there are thought to be many subpopulations of senescent cells in humans, each of them impairing tissue function in more or less the same way but requiring different interventions to remove them. If you can clear half of these senescent cell types then it'll take twice as long for the remaining ones to accumulate to levels that cause the same amount of trouble (assuming they each accumulate at the same rate). That's why incomplete damage repair can still extend lifespan, so long as some of the damage of each type can be repaired.

An important corollary of all this is that extending life expectancy from 150 to 1000 is much, much easier than going from 85 to 150. Let's say we manage to boost life expectancy to 150 while the oldest generational cohort are about 120. Perhaps you've learned to repair about 50% of damage subtypes in each category, so the overall rate of ageing has halved. But to half the rate of ageing a second time, you only need to learn to fix the next 25% of damage - with the benefit of all the knowledge, experience and infrastructure you've already grown. Cracking the next 12.5% doubles life expectancy a third time. An easier way to see this perhaps is that - if you ignore non-age-related mortality - lifespan must asymptote toward infinity as we approach comprehensive damage repair. But the portfolio of damage we must fix is finite, so lifespan must extend faster and faster as we approach completion.
 

The War On Ageing

So how long before we stop dying? The problem with timeframes is that they depend on what people actually do, and that in turn depends on where money is invested. There is a sense in which timeframe predictions may be self-fulfilling: if people think LEV is near then they're going to be more inclined to invest funds and careers in that direction. Your guess is as good as mine really, but intuitively, I feel like reaching LEV by 2040 is possible, if society commits to a full scale, government funded war on ageing. At some point, I think this will happen. We're not going to suddenly stumble upon LEV with no idea it was about to happen - at some point, we will achieve laboratory results that make it undeniable that radical healthy life extension is feasible in humans.

Aubrey de Grey is currently pursuing such results full throttle at the Longevity Escape Velocity Foundation (LEVF), a longevity Manhattan Project aiming for such extreme life extension in mice that the achievability of LEV in humans becomes undeniable. Their goal is to extend the mean and maximum lifespans of mice that normally live to 30 months by at least 12 months, with interventions that are initiated no later than 18 months of age. Recently they acquired 1000 pre-aged mice, and will be testing various combinations of four interventions each of which have individually been established to extend mouse lifespan significantly. The experiment begins this month, January 2023. To the best of my knowledge this is the only combined therapy longevity study in existence, and it is funded entirely by philanthropy. Studies of this nature are very expensive, so if you want it to go faster, click here to throw money at LEVF. 

Alternatively, it may turn out that early damage repair therapies in humans are able to catalyze the appropriate enthusiasm, particularly if they clearly reverse some aspect of what people call "ageing itself", e.g. cognitive decline, reduced walking speed, grey hair, etc.. A lot of exciting stuff is in the pipeline^[37][22], and optimism around genuine rejuvenation could snowball if even a fraction of these elicit a modest broad spectrum rejuvenation effect in humans.

It's helpful to consider the COVID pandemic in this context. People in this community are well aware of the FDA's "invisible graveyard" problem, whereby their incentives punish them far more severely for deaths caused by hastily approving a dangerous product than for deaths caused by failing to approve something safe and effective. Unless that product is a COVID therapy. When the pandemic hit, we adopted a sort of wartime mentality. The perceived threat from COVID was great enough that the public actually gained a sense of urgency, and sure enough, there was political pressure to approve certain therapies far faster than would normally be the case. 

The infection fatality rate of SARS-CoV-2 is estimated at around 2%. The fatality rate of ageing is 100%.

However the War On Ageing begins, I think it's going to feel a bit like when COVID hit, but crazier. People are going to wake up one morning and realize that they have a terminal but soon-to-be-curable illness. Ageing will transform in people's minds, perhaps quite suddenly, from a depressing statistic that we all avoid thinking about to a screaming moral imperative. Longevity, or rejuvenation, or whatever name we settle on will come to dominate public discourse just as COVID did, the public will demand that rejuvenation therapies are funded and fast-tracked, every world government will have a plan of action to defeat ageing, and insane quantities of money will be unleashed - as is always the case in wartime. We will suddenly discover that we can move much faster than we thought we could.

Incidentally, there’s a good change that cryonics will finally gain acceptance and support once this happens. The difference between those who get cryonics and those who don’t is the anticipation of radical technological progress. Despite the entire history of humanity being defined by scientific and technological revolution, most people continue to believe that only slow, predictable, incremental progress is realistic, and that preserving people until we have the means to revive them is therefore delusional. This could change rather rapidly once society is frantically racing towards LEV, and a whole generational cohort realise that it’s not going to be quite fast enough to save them. Despite the utter contempt and ridicule reserved for cryonicists by the tiny fraction of society that acknowledges their existence, the field has made great strides over the decades, such that with a modest investment of actual funding, we could potentially save the lives of millions of people who would otherwise perish a few years before salvation arrives.

This is all happening sooner than you think. The concepts I've outlined in this essay are gaining traction rapidly; the idea that ageing is driven by accumulating damage that may be amenable to therapy has been pretty much accepted since The Hallmarks of Aging was published^[38], meanwhile the idea that targeting fundamental ageing processes can delay, prevent and reverse multiple age-related disorders simultaneously has also gained traction^[39][1]. Recently these ideas are even permeating into the corridors of power^[40][41][42], and the popular media^[43], and that's to say nothing of the explosive growth in new companies and investment funding^[44].
 

Conclusion

Motte: fundamental damage types that accumulate slowly in all humans are the root causes of age-related disease; multiple age-related diseases can be slowed, prevented and reversed simultaneously by targeting damage instead of the diseases themselves; several such therapies are already under development and could benefit humans within 5 years with sufficient focus, luck, and regulatory approval; ageing is not one thing, therefore combination therapies addressing multiple damage types will be necessary for serious lifespan extension.

Bailey: the SENS taxonomy of damage is comprehensive, i.e. all clinically relevant types of damage fall into one of its seven categories and are solvable by a plausible engineering approach already under development somewhere, fixing all of them will result in the indefinite extension of healthy life; an all-out, global War On Ageing is imminent; LEV could be be reached in a couple of decades (Aubrey's prediction); most of us will look better at 100 than we do today. 

There is a growing consensus that the processes we traditionally think of as “normal ageing” are in fact the root causes of the pathologies of late life, and that targeting these processes is the key to slowing, preventing and reversing age-related diseases. Ageing has traditionally been seen as off-limits to medicine, and that’s precisely why our progress against age-related disease has been so mediocre. This is finally starting to change: good shit is in the pipeline, with the first wave of bona-fide rejuvenation therapies making good progress and attitudes starting to shift in both academia and congress.

Rejuvenation is the sensible way to go about what we’ve been trying to do for decades, namely, curing the diseases of old age. Gerontology is no longer some esoteric field offering minor quality of life improvements in the elderly, rather, it’s going to be the lynchpin of modern medicine, and the single most important thing we can do to relieve pressure on health services. If we’re willing to spend billions researching a cure for Alzheimer’s, then we must focus that money on reversing the cellular and molecular damage that drives it (i.e. ageing), because that’s the only way to succeed. Medicine is supposed to save lives, and extending lives is the same thing - the stuff we call longevity biotech is just medicine that works.

In conclusion: fuck ageing, none of us signed up for this shit. It’s time to escape the Wheel of Samsara for real.

 

About me

My background is in computer vision and machine learning; here are some papers I published as a PhD / postdoc: https://scholar.google.com/citations?user=PJIQyL8AAAAJ&hl=en&oi=sra

I had the pleasure of attending both LessDeath (a sort of networking summer camp / workshop) and Longevity Summit Dublin (a conference) in 2022. A big part of why I did that was to get a sense for how widely embraced the damage repair paradigm is within the broader longevity movement, and hear some alternative viewpoints. I found some people objecting to specific technical points Aubrey has made, but damage repair itself seems to be pretty widely accepted. Both events were excellent and will be repeated at some point this year. It was at LessDeath that I met JackH [LW · GW], who posted Anti-Aging: State of the Art [LW · GW] here two years ago. That was what inspired me to write a post of my own, but with emphasis on the specific concepts that have caused me to become optimistic about the feasibility and timeframe of LEV. There’s a lot of stuff I didn’t talk about here, so please ask me stuff in the comments if you have questions. 

 

1. ^{^}

   Aging: a common driver of chronic diseases and a target for novel interventions  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852871/

2. ^{^}

   What is Geroscience?  https://www.afar.org/what-is-geroscience

3. ^{^}

   The Clinical Potential of Senolytic Drugs  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641223/

4. ^{^}

   TAME: a genuinely good use of 75 million dollars  https://www.researchgate.net/publication/336386513_TAME_a_genuinely_good_use_of_75_million_dollars

5. ^{^}

   DNA methylation age of human tissues and cell types  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015143/

6. ^{^}

   DNA methylation GrimAge strongly predicts lifespan and healthspan  https://pubmed.ncbi.nlm.nih.gov/30669119/

7. ^{^}

   Cellular senescence and the senescent secretory phenotype: therapeutic opportunities  https://pubmed.ncbi.nlm.nih.gov/23454759/

8. ^{^}

   An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963991/

9. ^{^}

   Senolytic drugs: from discovery to translation  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/

10. ^{^}

    The serial cultivation of human diploid strains  https://pubmed.ncbi.nlm.nih.gov/13905658/

11. ^{^}

    Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor  https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060301

12. ^{^}

    Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599595/

13. ^{^}

    Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice  https://pubmed.ncbi.nlm.nih.gov/33470505

14. ^{^}

    Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis  https://pubmed.ncbi.nlm.nih.gov/30612898/

15. ^{^}

    Senolytic treatment rescues blunted muscle hypertrophy in old mice  https://link.springer.com/article/10.1007/s11357-022-00542-2

16. ^{^}

    Senolytics Improve Physical Function and Increase Lifespan in Old Age  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082705/

17. ^{^}

    Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412088/

18. ^{^}

    Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796530/

19. ^{^}

    Age-Related Macular Degeneration: A Scientometric Analysis  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458325/

20. ^{^}

    Age-Related Macular Degeneration  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369215/

21. ^{^}

    Intravitreal anti-VEGF agents and cardiovascular risk  https://pubmed.ncbi.nlm.nih.gov/31848994/

22. ^{^}

    lifespan.io Rejuvenation Roadmap  https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/

23. ^{^}

    Kelsey Moody | Macular Degeneration  https://www.youtube.com/watch?v=CIIvKhJO-m8

24. ^{^}

    Thymic involution and rising disease incidence with age  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828591/

25. ^{^}

    Dr. Greg Fahy – Rejuvenating the Thymus to Prevent Age-related Diseases  https://www.lifespan.io/news/rejuvenating-the-thymus/

26. ^{^}

    Reversal of epigenetic aging and immunosenescent trends in humans  https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028

27. ^{^}

    Greg Fahy, Intervene Immune | Thymus Rejuvenation Progress Update  https://www.youtube.com/watch?v=KukRAXnNOJM (edited transcript: https://foresight.org/summary/greg-fahy-intervene-immune-thymus-rejuvenation-progress-update/)

28. ^{^}

    https://ourworldindata.org/causes-of-death#what-do-people-die-from

29. ^{^}

    7-Ketocholesterol in disease and aging  https://www.sciencedirect.com/science/article/pii/S2213231719311759?via%3Dihub

30. ^{^}

    Cyclodextrin dimers: A versatile approach to optimizing encapsulation and their application to therapeutic extraction of toxic oxysterols  https://pubmed.ncbi.nlm.nih.gov/33839224/

31. ^{^}

    Cyclodextrin dimers for the remediation of atherosclerotic plaque  https://www.atherosclerosis-journal.com/article/S0021-9150(22)00798-5/fulltext

32. ^{^}

    Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals  https://www.biorxiv.org/content/10.1101/808642v1

33. ^{^}

    Toward a unified theory of aging and regeneration  https://www.researchgate.net/publication/335454143_Toward_a_unified_theory_of_aging_and_regeneration

34. ^{^}

    Reprogramming to recover youthful epigenetic information and restore vision   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752134/

35. ^{^}

    Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation  https://pubmed.ncbi.nlm.nih.gov/24529372/

36. ^{^}

    Partial reprogramming deep dive: the good, bad, and partially unresolved  https://www.adanguyenx.com/blog/partial-reprogramming

37. ^{^}

    https://agingbiotech.info/companies/

38. ^{^}

    The Hallmarks of Aging  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/

39. ^{^}

    Extending human healthspan and longevity: a symposium report  https://pubmed.ncbi.nlm.nih.gov/34498278/

40. ^{^}

    The Fountain of Youth? The Quest for Aging Therapies (Subcommittee on Investigations and Oversight)  https://youtu.be/Sm5K7WqgsDQ?t=355

41. ^{^}

    Fountain of Youth Hearing Charter  https://science.house.gov/imo/media/doc/9.15.2022%20Fountain%20of%20Youth%20Hearing%20Charter.pdf

42. ^{^}

    James Kirkland on growing interest from political figures  https://www.youtube.com/watch?v=VxAZw1Xoa3g&t=2296s

43. ^{^}

    Tackling ageing may be best way to prevent multiple chronic conditions from developing in older people https://theconversation.com/tackling-ageing-may-be-best-way-to-prevent-multiple-chronic-conditions-from-developing-in-older-people-174645

44. ^{^}

    Jim Mellon: Longevity could be the best investment you ever make  https://longevity.technology/news/jim-mellon-longevity-could-be-the-best-investment-you-ever-make/

45. ^{^}

    Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599595/

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