This is interesting work, and I like seeing how your other writing (on gears-level models, constraints, etc) seems to lie behind your approach to this research.
That said, there’s a fair bit of evidence that most symptoms of aging—including the major age-related diseases—share a common root cause, or at least a common core pathway. Some kinds of evidence of this:
Most symptoms/diseases of aging are correlated—someone who has one early is likely to have others. Conceptually, if you do a factor analysis on aging symptoms, there’s one big factor for a bunch of diseases, even after controlling for the number of years one has lived. (“Aging clock” is a relevant piece of jargon here.)
At the cellular level, a lot of diseases of aging “look similar”, and involve similar pieces. There’s a decrease in cell count, increase in damaged proteins/DNA/fats, and inflammation. We see roughly this pattern in Alzheimers, atherosclerosis, muscle loss, and many others.
Certain simple interventions reliably produce many diseases of aging—for instance, progerias are single mutations which produce a whole “early aging” phenotype
Conversely, certain simple interventions reliably delay many diseases of aging—e.g. calorie restricted diets.
One interpretation of the idea of a “common core pathway” is an argument that there’s some single aging factor (SAF), which triggers various forms of damage, which in turn cause the major diseases of aging. Hence, fighting those intermediate forms of damage would be ultimately futile, while fixing the SAF would be a panacea, at least if followed by other treatments that fix lingering damage.
An alternative idea is that there are multiple aging factors (MAFs), each of which triggers a particular form of damage. The damage it triggers goes on to cause a range of other forms of damage, which cause still others, resulting in a damage chain reaction that causes the major diseases of aging. Under this model, there are many MAFs that can trigger this chain reaction, and it’s just the first one that’s responsible for kicking off the aging process.
The difference is that preventing or curing one MAF wouldn’t halt or prevent aging. Preventing one MAF still leaves you open to others. And since it’s not the MAF, but a self-reinforcing chain reaction of damage, that drives aging, curing the MAF wouldn’t reverse or halt the damage.
As an analogy, in the SAF model, aging is like a flood. It causes a range of problems: washing away buildings and roads, drowning deaths, erosion. Try to repair the buildings while the flood’s going on, and you’ll make little progress. But if you can stop the flooding, then you can repair all the damage it caused and be “good as new.”
By contrast, in the MAFs model, aging is like a collapsing building. It could be caused by many underlying problems: termites, an earthquake, a bomb, demolition, fire, rot, a flood. But once the process is underway, the building enters a feedback loop. The flood introduces mold, which leads to rot, which opens holes in the house to allow the entry of vermin, which cause support beams to sag, and increases the risk of a short-circuit that could cause a fire. At a certain point, the original cause (the flood) can vanish entirely, but the accumulated damage is just perpetuating itself, and you can only save the house by eliminating all the damage sources.
The MAFs model can also explain many forms of evidence you cite. Since any given MAF can kick off the damage chain reaction, you’d expect the diseases caused by that damage to be correlated, though perhaps with some “leading” and the others “following” in any given case. The types of damage would be common, so you’d see common damage symptoms. You’d expect to see that certain interventions would cause the whole phenotype (an early MAF causes an early damage chain reaction).
The harder one to explain is the interventions that delay diseases of aging. Why should one intervention avoid many MAFs, unless all those MAFs had an underlying SAF that caused them all? So the crux of the MAF vs. SAF models seems to be whether calorie restricted diets (or other similar interventions) really work.
In dynamical system terms, I’d call the MAF scenario a single bistable feedback loop with many redundant components. (“Redundant” in the sense that many component subsets are sufficient to support the bistable feedback loop.) The senescence feedback loop is an example of this: there’s multiple components, and only a subset are needed to support the state change. For instance, either mitochondrial dysfunction or transposon activation would be sufficient to trigger the state change, and either one will cause the other once the state change is triggered.
So just because there’s one core feedback loop underlying all these core diseases, does not mean that there’s one root cause which activates that feedback loop.
There are reasons to believe there’s one root cause (or at least very few), but as you point out, these do not fully overlap with the reasons to believe there’s one core feedback loop. The main reason I expect one/few root cause(s) is that things which are out-of-equilibrium on the timescale of human aging are really rare in biological systems. The vast majority turn over much faster. So there just aren’t that many things which could be root causes.
Calorie restriction and the like do provide additional evidence, though I actually don’t think these provide particularly strong evidence for one/few root cause—not because it’s unclear whether they actually work (CR is one of the best-replicated findings in the field), but because they might just slow down the core feedback loop without directly touching the root cause(s). It is very likely that the core feedback loop itself accelerates the root cause(s), based on the exponential-acceleration pattern of the major age-related diseases, so slowing down the core feedback loop should slow down the root cause(s) too (though not reverse them or slow them down below the rate at which they progress in youth).
I like seeing how your other writing (on gears-level models, constraints, etc) seems to lie behind your approach to this research.
It was actually the other way around—I studied aging (among many other things) first, and those systems were what I drew on to understand gears, abstraction, constraints, etc.
This is interesting work, and I like seeing how your other writing (on gears-level models, constraints, etc) seems to lie behind your approach to this research.
One interpretation of the idea of a “common core pathway” is an argument that there’s some single aging factor (SAF), which triggers various forms of damage, which in turn cause the major diseases of aging. Hence, fighting those intermediate forms of damage would be ultimately futile, while fixing the SAF would be a panacea, at least if followed by other treatments that fix lingering damage.
An alternative idea is that there are multiple aging factors (MAFs), each of which triggers a particular form of damage. The damage it triggers goes on to cause a range of other forms of damage, which cause still others, resulting in a damage chain reaction that causes the major diseases of aging. Under this model, there are many MAFs that can trigger this chain reaction, and it’s just the first one that’s responsible for kicking off the aging process.
The difference is that preventing or curing one MAF wouldn’t halt or prevent aging. Preventing one MAF still leaves you open to others. And since it’s not the MAF, but a self-reinforcing chain reaction of damage, that drives aging, curing the MAF wouldn’t reverse or halt the damage.
As an analogy, in the SAF model, aging is like a flood. It causes a range of problems: washing away buildings and roads, drowning deaths, erosion. Try to repair the buildings while the flood’s going on, and you’ll make little progress. But if you can stop the flooding, then you can repair all the damage it caused and be “good as new.”
By contrast, in the MAFs model, aging is like a collapsing building. It could be caused by many underlying problems: termites, an earthquake, a bomb, demolition, fire, rot, a flood. But once the process is underway, the building enters a feedback loop. The flood introduces mold, which leads to rot, which opens holes in the house to allow the entry of vermin, which cause support beams to sag, and increases the risk of a short-circuit that could cause a fire. At a certain point, the original cause (the flood) can vanish entirely, but the accumulated damage is just perpetuating itself, and you can only save the house by eliminating all the damage sources.
The MAFs model can also explain many forms of evidence you cite. Since any given MAF can kick off the damage chain reaction, you’d expect the diseases caused by that damage to be correlated, though perhaps with some “leading” and the others “following” in any given case. The types of damage would be common, so you’d see common damage symptoms. You’d expect to see that certain interventions would cause the whole phenotype (an early MAF causes an early damage chain reaction).
The harder one to explain is the interventions that delay diseases of aging. Why should one intervention avoid many MAFs, unless all those MAFs had an underlying SAF that caused them all? So the crux of the MAF vs. SAF models seems to be whether calorie restricted diets (or other similar interventions) really work.
Great comments!
In dynamical system terms, I’d call the MAF scenario a single bistable feedback loop with many redundant components. (“Redundant” in the sense that many component subsets are sufficient to support the bistable feedback loop.) The senescence feedback loop is an example of this: there’s multiple components, and only a subset are needed to support the state change. For instance, either mitochondrial dysfunction or transposon activation would be sufficient to trigger the state change, and either one will cause the other once the state change is triggered.
So just because there’s one core feedback loop underlying all these core diseases, does not mean that there’s one root cause which activates that feedback loop.
There are reasons to believe there’s one root cause (or at least very few), but as you point out, these do not fully overlap with the reasons to believe there’s one core feedback loop. The main reason I expect one/few root cause(s) is that things which are out-of-equilibrium on the timescale of human aging are really rare in biological systems. The vast majority turn over much faster. So there just aren’t that many things which could be root causes.
Calorie restriction and the like do provide additional evidence, though I actually don’t think these provide particularly strong evidence for one/few root cause—not because it’s unclear whether they actually work (CR is one of the best-replicated findings in the field), but because they might just slow down the core feedback loop without directly touching the root cause(s). It is very likely that the core feedback loop itself accelerates the root cause(s), based on the exponential-acceleration pattern of the major age-related diseases, so slowing down the core feedback loop should slow down the root cause(s) too (though not reverse them or slow them down below the rate at which they progress in youth).
It was actually the other way around—I studied aging (among many other things) first, and those systems were what I drew on to understand gears, abstraction, constraints, etc.