Homeostasis and “Root Causes” in Aging

Great question, and it's a very subtle point.

In general, the "state variables" in biology are counts of identical things (or at least functionally-identical things). So for instance, paralleling your Harry Potter example, DNA is constantly breaking and being repaired. But the imperfections in that repair process aren't continuous - either the repair is perfect, or a mutation is introduced. Once a mutation is introduced (assuming it's in something functionally important), we have a functionally different molecule, so it needs to be reflected in a state variable: we need to have a state variable like "mutation count" or counts of specific kinds of mutations. That state variable will be what's out-of-steady-state on a long (in this case infinite) timescale.

This generalizes: if there are slight differences accumulating over time, then those will have a state variable (like mutation count), and that variable will be out-of-steady-state on a long timescale.

I remember that first paper which found some sort of flush-out mechanism for the brain opening up during deep sleep. Do you have a link? I've been meaning to dig into that a bit more. I remember when I first saw it I thought it would be huge for understanding Alzheimers, but that was a while ago before I started seriously reading up on aging.

Anyway, environmental factors...

There's a qualitative general pattern that various kinds of physiological stress - exposure to radiation or harsh chemicals (including smoking), chronic infection, malnutrition, sleep deprivation, etc - tend to accelerate aging. These are results which I generally don't put too much faith in, at least individually - they're too flashy, so there's likely publication bias. That said, there is a plausible mechanism by which general physiological insults would accelerate aging. I'll save discussion of that for a later post, but David Sinclair published a (general-audience) book earlier this year which discusses it quite a bit.

One important thing to note, more related to the OP: whatever the root causes of aging are, i.e. the things which are out-of-equilibrium on long timescales, those do need to be internal to the organism. We would have noticed centuries ago if changing the environment could forestall aging long-term. That does not mean these factors need to be inside particular cells; for instance, extracellular aggregation of certain long-lived proteins is one plausible root cause (e.g. elastin deposits as a cause of wrinkles [LW · GW]). It is very likely that we are still missing connections in the causal graph, so there could easily be things building up that we're not paying attention to yet. That said, there are relatively few things in the body which turn over on decade-plus timescales, so that severely limits the list of possible root causes.

Alzheimer's, and several other age-related diseases, seem to be related to lifestyle, since they're rare enough in hunter-gatherer tribes that they can't be detected.

The kinds of age-related deaths that are common to all environments are mainly due to frailty, susceptibility to infectious diseases, and cancer.

Yeah, lots of sources say that various aging-related things "accumulate". If you dig into it, it turns out that by "accumulate" they usually mean "increases" - DNA damage does not actually stick around for long, it turns over very quickly (see e.g. here, or compare the damage frequencies to the steady state levels on the wikipedia page). But the steady-state level of DNA damage does increase with age (even in many types of replicating cells), so either the damage rate increases or the repair rate decreases.

Weakening of muscles is an interesting case. Muscle "cells" (myocytes) are really huge, centimeter-long super-cells containing hundreds of nuclei, and satellite cells (the first type of stem cell discovered) spin off new nuclei to add to the myocyte on an as-needed basis. So although the cell itself is technically long-lived, that doesn't mean the components - even including the DNA - aren't replaced. Loss of muscle mass (sarcopenia) is considered one of the main hallmarks of aging, but as far as I can tell, the gears of sarcopenia are still quite poorly understood. (A lot of people spent a lot of time and effort imaging neuromuscular junctions, but that seems to have been driven more by the desire to publish pretty pictures than by any actual evidence that NMJs play a causal role in sarcopenia.)

Telomere shortening is an interesting case. (I'm going to give my current understanding here without trying to dig up references, so take it all with a grain of salt.)

It's clearly a plausible root cause - it's a change which could stick around on long enough timescales to account for aging. On the other hand, it is possible for telomeres to turn over: telomerase is active in stem cells, so telomere length should at least not be an issue for cell types which regularly turn over - the telomeres turn over with the cells, which are ultimately replaced from the stem cells. For long-lived cells, there's a stronger case that telomere shortening could be an issue.

Telomeres do get shorter with age, BUT they get shorter even in cell types which turn over regularly. That's a bit of a red flag - either the telomeres aren't being fully replaced by telomerase in the stem cells (in which case the stem cells ought to die a lot sooner), or some other mechanism is making them short besides accumulated loss over lifetime. The alternative mechanism which jumps out to me is: DNA damage, and oxidative damage in particular, has been observed to rapidly shorten telomeres. DNA damage and oxidative damage rates are generally observed to be much higher in aged cells of most types, so that would explain why telomeres are shorter in older organisms.

In terms of actual experiments, telomerase-boosters have been experimented with a fair bit, and my understanding is that they don't have much effect on age-related diseases (though of course there's the usual pile of low-N studies which find barely-significant and blatantly p-hacked results).

Other things will eventually be covered later in this sequence.

Correct. However, even in that case, the overall level would still reach a steady-state on a timescale much faster than aging itself. More generally, feedback loops equilibrate on roughly the timescale of their slowest component. So, even if there's a feedback loop in the mix, it still can't be a root cause of aging unless one of the components is out-of-equilibrium on a timescale comparable to aging (i.e. decades or longer).