Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio.
This is: Core Pathways of Aging, published by johnswentworth on the LessWrong.
Most overviews of aging suffer from multiple problems:
They dump a bunch of findings with no high-level picture.
Many of the claims they make are outdated, purely theoretical, and sometimes even outright disproven by existing work.
They are usually written by working academics, who are shy about telling us when their peers’ work is completely wrong.
They are shy about making strong claims, since this would also implicitly mean denying some claims of the authors’ peers.
This post is a high-level brain-dump of my current best models of the core pathways of aging, as I currently understand them. I have no particular reason to avoid calling out claims I think are wrong/irrelevant, and I’m going to present high-level models without pages and pages of disclaimers and discussions about results which maybe disagree with them (but are probably just wrong/irrelevant).
Epistemic status: I would be surprised if none of it turned out to be wrong, but there are multiple lines of evidence supporting most claims. It is not highly polished, and references are included only when I have them readily on hand. My ideal version of this piece would have more detailed references, more double-checking behind the claims, and more direct presentation of the data which backs up each claim. Unfortunately, that would take enough time and effort that I’m unlikely to actually get to it soon. So. here’s what I could produce in a reasonable amount of time. Hopefully it will be wrong/unhelpful in ways orthogonal to how most overviews are wrong/unhelpful.
Foundations
First, let’s recap a couple foundational principles. I’ll go through these pretty quickly; see the linked posts for more info.
Homeostasis and “Root Causes” in Aging: the vast majority of proteins, cells, etc, in the human body turn over on a timescale from days to months. At any given time, their level (e.g. protein concentration, cell count, etc) is in equilibrium on the turnover timescale - i.e. the rate of creation approximately equals the rate of removal. For any X with turnover much faster than aging (i.e. decades), if we see the level of X increase/decrease on the timescale of a human lifetime, then that is not due to permanent “accumulation of X” or “depletion of X”; it is due to increase/decrease in the rate of creation/removal of X. For instance:
DNA damage is typically repaired on a timescale of hours or faster, depending on the type. If DNA damage levels increase with age, that is due to an increase in rate of damage or decrease in rate of repair, not permanent accumulation.
Typical senescent cells turn over on a timescale of days to weeks. If the number of senescent cells increases with age, that is due to an increase in rate of senescent cell production or decrease in rate of removal, not permanent accumulation.
Elastin is believed to not turn over at all in humans. So if we see elastin deposits increasing with age (e.g. in wrinkles), then that could be permanent accumulation.
Furthermore: suppose we have a positive feedback cycle. Increasing A decreases the rate of production of B, so B decreases. But decreasing B decreases the rate of removal of A, so A increases. If both A and B individually turn over on a timescale of hours or faster then this feedback loop as a whole will also typically operate on a timescale of hours or faster - i.e. count/concentration of A will explode upward on roughly that timescale. More generally, a feedback loop will usually operate on the timescale of its slowest component, exactly like the rate-limiting step of a chemical reaction.
Main upshot of all this: since aging involves changes on a timescale of decades, there must be some component which is out-of-equilibrium on a timescale of decades or longer (i.e. does not turn ove...
view more