Let’s start with a stylized fact: almost every cell type in the human body is removed and replaced on a regular basis. The frequency of this turnover ranges from a few days (for many immune cells and cells in the gastrointestinal lining) to ten years (for fat, heart, and skeleton cells). Only a handful of tissues are believed to be non-renewing in humans - e.g. eggs, neurons, and the lens of the eye (and even out of those, neurons are debatable).
This means that the number of cells of any given type is determined by “homeostatic equilibrium” - the balance of cell removal and replacement. If an ulcer destroys a bunch of cells in your stomach lining, they’ll be replaced over a few days, and the number of stomach cells will return to roughly the same equilibrium level as before. If a healthy person receives a bunch of extra red blood cells in a transfusion, they’ll be broken down over a few months, and the number of blood cells will return to roughly the same equilibrium level as before.
As organisms age, we see a change in the homeostatic equilibrium level of many different cell types (and other parameters, like hormone and cytokine levels). In particular, a wide variety of symptoms of aging involve “depletion” (i.e. lower observed counts) of various cell types.
However, human aging happens on a very slow timescale, i.e. decades. Most cell counts equilibrate much faster - for instance, immune cell counts equilibrate on a scale of days to weeks. So, suppose we see a decrease in the count of certain immune cells with age - e.g. naive T cells. Could it be that naive T cells just wear out and die off with age? No - T cells are replaced every few weeks, so a change on a timescale of decades cannot be due to the cells themselves dying off. If the count of naive T cells falls on a timescale of decades, then either (a) the rate of new cell creation has decreased, or (b) the rate of old cell removal has increased (or both). Either of those would require some “upstream” change to cause the rate change.
More generally: in order for cell counts, or chemical concentrations, or any other physiological parameter to decrease/increase with age, at least one of the following must be true:
- the timescale of turnover is on the order of decades (or longer)
- rate of removal increases/decreases
- rate of creation decreases/increases
If none of these is true, then any change is temporary - the cell count/concentration/whatever will return to the same level as before, determined by the removal and creation rates.
Of those three possibilities, notice that the second two - increase/decrease in production/removal rate - both imply some other upstream cause. Something else must have caused the rate change. Sooner or later, that chain of cause-and-effect needs to bottom out, and it can only bottom out in something which equilibrates on a timescale of decades or longer. (Feedback loops are possible, but if all the components equilibrate on a fast timescale then so will the loop.) Something somewhere in the system is out-of-equilibrium on a timescale of decades. We’ll call that thing (or things) a “root cause” of aging. It’s something which is not replaced on a timescale faster than decades, and it either accumulates or decumulates with age.
Now, the main criteria: a root cause of aging cannot be a higher or lower value of any parameter subject to homeostasis on a faster timescale than aging itself. Examples:
- Most cell types turn over on timescales of days to months. “Depletion” of any of these cell types cannot be a root cause of aging; either their production rate has decreased or their removal rate has increased.
- DNA damage (as opposed to mutation) is normally repaired on a timescale of hours - sometimes much faster, depending on type. “Accumulation” of DNA damage cannot be a root cause of aging; either the rate of new damage has increased or the repair rate has decreased.
- DNA mutations cannot be repaired; from a cell’s perspective, the original information is lost. So mutations can accumulate in a non-equilibrium fashion, and are a plausible root cause under the homeostasis argument.
Note that the homeostasis argument does not mean the factors ruled out above are not links in the causal chain. For instance, there’s quite a bit of evidence that DNA damage does increase with age, and that this has important physiological effects. However, there must be changes further up the causal chain - some other long-term change in the organism’s state leads to faster production or slower repair of DNA damage. Conversely, the homeostasis argument does not imply that “plausible root causes” are the true root causes - for instance, although DNA mutations could accumulate in principle, cells with certain problematic mutations are believed to be cleared out by the immune system - so the number of cells with these mutations is in equilibrium on a fast timescale, and cannot be a root cause of aging.
For any particular factor which changes with age, key questions are:
- Is it subject to homeostasis?
- If so, on what timescale does it turn over?
- If it is subject to homeostasis on a timescale faster than aging, then what are the production and removal mechanisms, and what changes the production and removal rates with age?
These determine the applicability of the homeostasis argument. Typically, anything which can normally be fixed/replaced/undone by the body will be ruled out as a root cause of aging - the timescale of aging is very long compared to practically all other physiological processes. We then follow the causal chain upstream, in search of plausible root cause.