Here’s a side project David and I have been looking into, which others might have useful input on...
Background: Thyroid & Cortisol Systems
As I understand it, thyroid hormone levels are approximately-but-accurately described as the body’s knob for adjusting “overall metabolic rate” or the subjective feeling of needing to burn energy. Turn up the thyroid knob, and people feel like they need to move around, bounce their leg, talk fast, etc (at least until all the available energy sources are burned off and they crash). Turn down the thyroid knob, and people are lethargic.
That sounds like the sort of knob which should probably typically be set higher, today, than was optimal in the ancestral environment. Not cranked up to 11; hyperthyroid disorders are in fact dangerous and unpleasant. But at least set to the upper end of the healthy range, rather than the lower end.
… and that’s nontrivial. You can just dump the relevant hormones (T3/T4) into your body, but there’s a control system which tries to hold the level constant. Over the course of months, the thyroid gland (which normally produces T4) will atrophy, as it shrinks to try to keep T4 levels fixed. Just continuing to pump T3/T4 into your system regularly will keep you healthy—you’ll basically have a hypothyroid disorder, and supplemental T3/T4 is the standard treatment. But you better be ready to manually control your thyroid hormone levels indefinitely if you start down this path. Ideally, one would intervene further up the control loop in order to adjust the thyroid hormone set-point, but that’s more of a research topic than a thing humans already have lots of experience with.
So that’s thyroid. We can tell a similar story about cortisol.
As I understand it, the cortisol hormone system is approximately-but-accurately described as the body’s knob for adjusting/tracking stress. That sounds like the sort of knob which should probably be set lower, today, than was optimal in the ancestral environment. Not all the way down; problems would kick in. But at least set to the lower end of the healthy range.
… and that’s nontrivial, because there’s a control loop in place, etc. Ideally we’d intervene on the relatively-upstream parts of the control loop in order to change the set point.
We’d like to generalize this sort of reasoning, and ask: what are all the knobs of this sort which we might want to adjust relative to their ancestral environment settings?
Generalization
We’re looking for signals which are widely broadcast throughout the body, and received by many endpoints. Why look for that type of thing? Because the wide usage puts pressure on the signal to “represent one consistent thing”. It’s not an accident that there are individual hormonal signals which are approximately-but-accurately described by the human-intuitive phrases “overall metabolic rate” or “stress”. It’s not an accident that those hormones’ signals are not hopelessly polysemantic. If we look for widely-broadcast signals, then we have positive reason to expect that they’ll be straightforwardly interpretable, and therefore the sort of thing we can look at and (sometimes) intuitively say “I want to turn that up/down”.
Furthermore, since these signals are widely broadcast, they’re the sort of thing which impacts lots of stuff (and is therefore impactful to intervene upon). And they’re relatively easy to measure, compared to “local” signals.
The “wide broadcast” criterion helps focus our search a lot. For instance, insofar as we’re looking for chemical signals throughout the whole body, we probably want species in the bloodstream; that’s the main way a concentration could be “broadcast” throughout the body, rather than being a local signal. So, basically endocrine hormones.
Casting a slightly wider net, we might also be interested in:
Signals widely broadcast through the body by the nervous system.
Chemical signals widely broadcast through the brain specifically (since that’s a particularly interesting/relevant organ).
Non-chemical signals widely broadcast through the brain specifically.
… and of course for all of these there will be some control system, so each has its own tricky question about how to adjust it.
Some Promising Leads, Some Dead Ends
With some coaxing, we got a pretty solid-sounding list of endocrine hormones out of the LLMs. There were some obvious ones on the list, including thyroid and cortisol systems, sex hormones, and pregnancy/menstruation signals. There were also a lot of signals for homeostasis of things we don’t particularly want to adjust: salt balance, calcium, digestion, blood pressure, etc. There were several inflammation and healing signals, which we’re interested in but haven’t dug into yet. And then there were some cool ones: oxytocin (think mother-child bonding), endocannabinoids (think pot), satiety signals (think Ozempic). None of those really jumped out as clear places to turn a knob in a certain direction, other than obvious things like “take ozempic if you are even slightly overweight” and the two we already knew about (thyroid and cortisol).
Then there were neuromodulators. Here’s the list we coaxed from the LLMs:
Dopamine: Tracks expected value/reward—how good things are compared to expectations.
Norepinephrine: Sets arousal/alertness level—how much attention and energy to devote to the current situation.
Serotonin: Regulates resource availability mindset—whether to act like resources are plentiful or scarce. Affects patience, time preference, and risk tolerance.
Acetylcholine: Controls signal-to-noise ratio in neural circuits—acts like a gain/precision parameter, determining whether to amplify precise differences (high ACh) or blur things together (low ACh).
Histamine: Manages the sleep/wake switch—promotes wakefulness and suppresses sleep when active.
Orexin: Acts as a stability parameter for brain states—increases the depth of attractor basins and raises transition barriers between states. Higher orexin = stronger attractors = harder to switch states.
Of those, serotonin immediately jumps out as a knob you’d probably want to turn to the “plentiful resources” end of the healthy spectrum, compared to the ancestral environment. That puts the widespread popularity of SSRIs in an interesting light!
Moving away from chemical signals, brain waves (alpha waves, theta oscillations, etc) are another potential category—they’re oscillations at particular frequencies which (supposedly) are widely synced across large regions of the brain. I read up just a little, and so far have no idea how interesting they are as signals or targets.
Shifting gears, the biggest dead end so far has been parasympathetic tone, i.e. overall activation level of the parasympathetic nervous system. As far as I can tell, parasympathetic tone is basically Not A Thing: there are several different ways to measure it, and the different measurements have little correlation. It’s probably more accurate to think of parasympathetic nervous activity as localized, without much meaningful global signal.
Uh… Guys. Uh. Biology is complicated. It’s a messy pile of spaghetti code. Not that it’s entirely intractable to make Pareto improvements but, watch out for unintended consequences.
For instance: you are very wrong about cortisol. Cortisol is a “stress response hormone”. It tells the body to divert resources to bracing itself to deal with stress (physical and/or mental). Experiments have shown that if you put someone through a stressful event while suppressing their cortisol, they have much worse outcomes (potentially including death).
Cortisol doesn’t make you stressed, it helps you survive stress. Deviation from homeostatic setpoints (including mental ones) are what make you stressed.
Hmm, I’ll see if I can find some old papers.… I’m just reciting memories from grad school lectures like… 12 years ago.
Here’s an example of the finding being replicated and explored further in a primate model: https://www.jci.org/articles/view/112443
Basically, cortisol is helpful for surviving injuries. Is it helpful for mental stress? Unclear.
Long term high cortisol is harmful, but the stress in one’s life resulting in that high cortisol level is harmful in more ways than just high cortisol. So are there times when it would be helpful to reduce someone’s cortisol level? Absolutely. But it’s complicated and should be done thoughtfully and selectively, and in combination with other things (particularly seeking out and treating the upstream causes).
I don’t think that any of {dopamine, NE, serotonin, acetylcholine} are scalar signals that are “widely broadcast through the brain”. Well, definitely not dopamine or acetylcholine, almost definitely not serotonin, maybe NE. (I recently briefly looked into whether the locus coeruleus sends different NE signals to different places at the same time, and ended up at “maybe”, see §5.3.1 here for a reference.)
I don’t know anything about histamine or orexin, but neuropeptides are a better bet in general for reasons in §2.1 here.
As far as I can tell, parasympathetic tone is basically Not A Thing
Yeah, I recall reading somewhere that the term “sympathetic” in “sympathetic nervous system” is related to the fact that lots of different systems are acting simultaneously. “Parasympathetic” isn’t supposed to be like that, I think.
We’re looking for signals which are widely broadcast throughout the body, and received by many endpoints. Why look for that type of thing? Because the wide usage puts pressure on the signal to “represent one consistent thing”. It’s not an accident that there are individual hormonal signals which are approximately-but-accurately described by the human-intuitive phrases “overall metabolic rate” or “stress”. It’s not an accident that those hormones’ signals are not hopelessly polysemantic. If we look for widely-broadcast signals, then we have positive reason to expect that they’ll be straightforwardly interpretable, and therefore the sort of thing we can look at and (sometimes) intuitively say “I want to turn that up/down”.
This sounds logical but I don’t think is backed empirically, at least to the degree you’re claiming. Source: I have a biology BA and can’t speak directly to the question because I never took those classes because they had reputations for being full of exceptions and memorization.
I don’t have deep expertise in the subject, but I’m inclined to concur with the people saying that the widely broadcast signals don’t actually represent one consistent thing, despite your plausible argument to the contrary.
Here’s a Scott Alexander post speculating why that might be the case. In short: there was an optimization pressure towards making internal biological signals very difficult to decode, because easily decodable signals were easy target for parasites evolving to exploit them. As the result, the actual signals are probably represented as “unnecessarily” complicated, timing-based combinations of various “basic” chemical, electrical, etc. signals, and they’re somewhat individualized to boot. You can’t decode them just by looking at any one spatially isolated chunk of the body, by design.
Basically: separate chemical substances (and other components that look “simple” locally/from the outside) are not the privileged basis for decoding internal signals. They’re the anti-privileged basis, if anything.
Yeah but if something is in the general circulation (bloodstream), then it’s going everywhere in the body. I don’t think there’s any way to specifically direct it.
…Except in the time domain, to a limited extent. For example, in rats, tonic oxytocin in the bloodstream controls natriuresis, while pulsed oxytocin in the bloodstream controls lactation and birth. The kidney puts a low-pass filter on its oxytocin detection system, and the mammary glands & uterus put a high-pass filter, so to speak.
Yeah but if something is in the general circulation (bloodstream), then it’s going everywhere in the body. I don’t think there’s any way to specifically direct it.
The point wouldn’t be to direct it, but to have different mixtures of chemicals (and timings) to mean different things to different organs.
Loose analogy: Suppose that the intended body behaviors (“kidneys do X, heart does Y, brain does Z” for all combinations of X, Y, Z) are latent features, basic chemical substances and timings are components of the input vector, and there are dramatically more intended behaviors than input-vector components. Can we define the behavior-controlling function of organs (distributed across organs) such that, for any intended body behavior, there’s a signal that sets the body into approximately this state?
It seems that yes. The number of almost-orthogonal vectors in d dimensions scales exponentially with d, so we simply need to make the behavior-controlling function sensitive to these almost-orthogonal directions, rather than the chemical-basis vectors. The mappings from the input vector to the output behaviors, for each organ, would then be some complicated mixtures, not a simple “chemical A sets all organs into behavior X”.
This analogy seems flawed in many ways, but I think something directionally-like-this might be happening?
Just because the number of almost-orthogonal vectors in d dimensions scales exponentially with d, doesn’t mean one can choose all those signals independently. We can still only choose d real-valued signals at a time (assuming away the sort of tricks by which one encodes two real numbers in a single real number, which seems unlikely to happen naturally in the body). So “more intended behaviors than input-vector components” just isn’t an option, unless you’re exploiting some kind of low-information-density in the desired behaviors (like e.g. very “sparse activation” of the desired behaviors, or discreteness of the desired behaviors to a limited extent).
The above toy model assumed that we’re picking one signal at a time, and that each such “signal” specifies the intended behavior for all organs simultaneously...
… But you’re right that the underlying assumption there was that the set of possible desired behaviors is discrete (i. e., that X in “kidneys do X” is a discrete variable, not a vector of reals). That might’ve indeed assumed me straight out of the space of reasonable toy models for biological signals, oops.
I had seen recommendations for T3/T4 on twitter to help with low energy, and even purchased some, but haven’t taken it. I hadn’t considered that the thyroid might respond by shrinking, and now think that that’s a worrying intervention! So I’m glad I read this—thank you.
As someone who has Graves’ Disease … one of the reasons that you really don’t want to run your metabolism faster with higher T4 levels is that higher heart rate for an extended period can cause your heart to fail.
More generally: changing the set point of any of these system might cause the failure of some critical component that depends on the old value of the set point,
Yup, I’m familiar with that one. The big difference is that I’m backward-chaining, whereas that post forward chains; the hope of backward chaining would be to identify big things which aren’t on peoples’ radar as nootropics (yet).
(Relatedly: if one is following this sort of path, step 1 should be a broad nutrition panel and supplementing anything in short supply, before we get to anything fancier.)
So I find the question underspecified, why do you want this?
Why are you decomposing body signalling without looking at the major sub-regulstort systems? If you want to predict sleep then cortisol, melatonin, etc. is something quite good and this will tell you about stress regulation which effects both endocrine as well as cortisol systems.
If you want to look at nutritional systems then GLP-1 activation is good for average food need whilst grelin is predictive of whether you will feel hungry at specific times.
If you’re looking at brain health then serotonin activation patterns can be really good to check but this is different from how the stomach uses it and it does have the majority of serotonin. But this is like way to simplified especially for the brain.
Different subsystems use the same molecules in different ways, waste not and all that so what are you looking for and why?
Is there a particular reason to not include sex hormones? Some theories suggest that testosterone tracks relative social status. We might expect that high social status → less stress (of the cortisol type) + more metabolic activity. Since it’s used by trans people we have a pretty good idea of what it does to you at high doses (makes you hungry, horny, and angry) but its unclear whether it actually promotes low cortisol-stress and metabolic activity.
Here’s a side project David and I have been looking into, which others might have useful input on...
Background: Thyroid & Cortisol Systems
As I understand it, thyroid hormone levels are approximately-but-accurately described as the body’s knob for adjusting “overall metabolic rate” or the subjective feeling of needing to burn energy. Turn up the thyroid knob, and people feel like they need to move around, bounce their leg, talk fast, etc (at least until all the available energy sources are burned off and they crash). Turn down the thyroid knob, and people are lethargic.
That sounds like the sort of knob which should probably typically be set higher, today, than was optimal in the ancestral environment. Not cranked up to 11; hyperthyroid disorders are in fact dangerous and unpleasant. But at least set to the upper end of the healthy range, rather than the lower end.
… and that’s nontrivial. You can just dump the relevant hormones (T3/T4) into your body, but there’s a control system which tries to hold the level constant. Over the course of months, the thyroid gland (which normally produces T4) will atrophy, as it shrinks to try to keep T4 levels fixed. Just continuing to pump T3/T4 into your system regularly will keep you healthy—you’ll basically have a hypothyroid disorder, and supplemental T3/T4 is the standard treatment. But you better be ready to manually control your thyroid hormone levels indefinitely if you start down this path. Ideally, one would intervene further up the control loop in order to adjust the thyroid hormone set-point, but that’s more of a research topic than a thing humans already have lots of experience with.
So that’s thyroid. We can tell a similar story about cortisol.
As I understand it, the cortisol hormone system is approximately-but-accurately described as the body’s knob for adjusting/tracking stress. That sounds like the sort of knob which should probably be set lower, today, than was optimal in the ancestral environment. Not all the way down; problems would kick in. But at least set to the lower end of the healthy range.
… and that’s nontrivial, because there’s a control loop in place, etc. Ideally we’d intervene on the relatively-upstream parts of the control loop in order to change the set point.
We’d like to generalize this sort of reasoning, and ask: what are all the knobs of this sort which we might want to adjust relative to their ancestral environment settings?
Generalization
We’re looking for signals which are widely broadcast throughout the body, and received by many endpoints. Why look for that type of thing? Because the wide usage puts pressure on the signal to “represent one consistent thing”. It’s not an accident that there are individual hormonal signals which are approximately-but-accurately described by the human-intuitive phrases “overall metabolic rate” or “stress”. It’s not an accident that those hormones’ signals are not hopelessly polysemantic. If we look for widely-broadcast signals, then we have positive reason to expect that they’ll be straightforwardly interpretable, and therefore the sort of thing we can look at and (sometimes) intuitively say “I want to turn that up/down”.
Furthermore, since these signals are widely broadcast, they’re the sort of thing which impacts lots of stuff (and is therefore impactful to intervene upon). And they’re relatively easy to measure, compared to “local” signals.
The “wide broadcast” criterion helps focus our search a lot. For instance, insofar as we’re looking for chemical signals throughout the whole body, we probably want species in the bloodstream; that’s the main way a concentration could be “broadcast” throughout the body, rather than being a local signal. So, basically endocrine hormones.
Casting a slightly wider net, we might also be interested in:
Signals widely broadcast through the body by the nervous system.
Chemical signals widely broadcast through the brain specifically (since that’s a particularly interesting/relevant organ).
Non-chemical signals widely broadcast through the brain specifically.
… and of course for all of these there will be some control system, so each has its own tricky question about how to adjust it.
Some Promising Leads, Some Dead Ends
With some coaxing, we got a pretty solid-sounding list of endocrine hormones out of the LLMs. There were some obvious ones on the list, including thyroid and cortisol systems, sex hormones, and pregnancy/menstruation signals. There were also a lot of signals for homeostasis of things we don’t particularly want to adjust: salt balance, calcium, digestion, blood pressure, etc. There were several inflammation and healing signals, which we’re interested in but haven’t dug into yet. And then there were some cool ones: oxytocin (think mother-child bonding), endocannabinoids (think pot), satiety signals (think Ozempic). None of those really jumped out as clear places to turn a knob in a certain direction, other than obvious things like “take ozempic if you are even slightly overweight” and the two we already knew about (thyroid and cortisol).
Then there were neuromodulators. Here’s the list we coaxed from the LLMs:
Dopamine: Tracks expected value/reward—how good things are compared to expectations.
Norepinephrine: Sets arousal/alertness level—how much attention and energy to devote to the current situation.
Serotonin: Regulates resource availability mindset—whether to act like resources are plentiful or scarce. Affects patience, time preference, and risk tolerance.
Acetylcholine: Controls signal-to-noise ratio in neural circuits—acts like a gain/precision parameter, determining whether to amplify precise differences (high ACh) or blur things together (low ACh).
Histamine: Manages the sleep/wake switch—promotes wakefulness and suppresses sleep when active.
Orexin: Acts as a stability parameter for brain states—increases the depth of attractor basins and raises transition barriers between states. Higher orexin = stronger attractors = harder to switch states.
Of those, serotonin immediately jumps out as a knob you’d probably want to turn to the “plentiful resources” end of the healthy spectrum, compared to the ancestral environment. That puts the widespread popularity of SSRIs in an interesting light!
Moving away from chemical signals, brain waves (alpha waves, theta oscillations, etc) are another potential category—they’re oscillations at particular frequencies which (supposedly) are widely synced across large regions of the brain. I read up just a little, and so far have no idea how interesting they are as signals or targets.
Shifting gears, the biggest dead end so far has been parasympathetic tone, i.e. overall activation level of the parasympathetic nervous system. As far as I can tell, parasympathetic tone is basically Not A Thing: there are several different ways to measure it, and the different measurements have little correlation. It’s probably more accurate to think of parasympathetic nervous activity as localized, without much meaningful global signal.
Anybody see obvious things we’re missing?
Uh… Guys. Uh. Biology is complicated. It’s a messy pile of spaghetti code. Not that it’s entirely intractable to make Pareto improvements but, watch out for unintended consequences.
For instance: you are very wrong about cortisol. Cortisol is a “stress response hormone”. It tells the body to divert resources to bracing itself to deal with stress (physical and/or mental). Experiments have shown that if you put someone through a stressful event while suppressing their cortisol, they have much worse outcomes (potentially including death). Cortisol doesn’t make you stressed, it helps you survive stress. Deviation from homeostatic setpoints (including mental ones) are what make you stressed.
This is interesting. Can you say more about these experiments?
Hmm, I’ll see if I can find some old papers.… I’m just reciting memories from grad school lectures like… 12 years ago. Here’s an example of the finding being replicated and explored further in a primate model: https://www.jci.org/articles/view/112443
Here’s a review of cortisol inhibition and surgery findings. A mixed bag, a complicated system. https://academic.oup.com/bja/article/85/1/109/263834
https://onlinelibrary.wiley.com/doi/abs/10.1111/ejn.15721 “Evidence suggests that psychological stress has effects on decision making, but the results are inconsistent, and the influence of cortisol and other modulating factors remains unclear. ”
Basically, cortisol is helpful for surviving injuries. Is it helpful for mental stress? Unclear. Long term high cortisol is harmful, but the stress in one’s life resulting in that high cortisol level is harmful in more ways than just high cortisol. So are there times when it would be helpful to reduce someone’s cortisol level? Absolutely. But it’s complicated and should be done thoughtfully and selectively, and in combination with other things (particularly seeking out and treating the upstream causes).
You can find lots more on Google scholar.
I don’t think that any of {dopamine, NE, serotonin, acetylcholine} are scalar signals that are “widely broadcast through the brain”. Well, definitely not dopamine or acetylcholine, almost definitely not serotonin, maybe NE. (I recently briefly looked into whether the locus coeruleus sends different NE signals to different places at the same time, and ended up at “maybe”, see §5.3.1 here for a reference.)
I don’t know anything about histamine or orexin, but neuropeptides are a better bet in general for reasons in §2.1 here.
Yeah, I recall reading somewhere that the term “sympathetic” in “sympathetic nervous system” is related to the fact that lots of different systems are acting simultaneously. “Parasympathetic” isn’t supposed to be like that, I think.
This sounds logical but I don’t think is backed empirically, at least to the degree you’re claiming. Source: I have a biology BA and can’t speak directly to the question because I never took those classes because they had reputations for being full of exceptions and memorization.
The most obvious one imo is the immune system & the signals it sends.
Others:
Circadian rhythm
Age is perhaps a candidate here, though it may be more or less a candidate depending on if you’re talking about someone before or after 30
Hospice workers sometimes talk about the body “knowing how to die”, maybe there’s something to that
I don’t have deep expertise in the subject, but I’m inclined to concur with the people saying that the widely broadcast signals don’t actually represent one consistent thing, despite your plausible argument to the contrary.
Here’s a Scott Alexander post speculating why that might be the case. In short: there was an optimization pressure towards making internal biological signals very difficult to decode, because easily decodable signals were easy target for parasites evolving to exploit them. As the result, the actual signals are probably represented as “unnecessarily” complicated, timing-based combinations of various “basic” chemical, electrical, etc. signals, and they’re somewhat individualized to boot. You can’t decode them just by looking at any one spatially isolated chunk of the body, by design.
Basically: separate chemical substances (and other components that look “simple” locally/from the outside) are not the privileged basis for decoding internal signals. They’re the anti-privileged basis, if anything.
Yeah but if something is in the general circulation (bloodstream), then it’s going everywhere in the body. I don’t think there’s any way to specifically direct it.
…Except in the time domain, to a limited extent. For example, in rats, tonic oxytocin in the bloodstream controls natriuresis, while pulsed oxytocin in the bloodstream controls lactation and birth. The kidney puts a low-pass filter on its oxytocin detection system, and the mammary glands & uterus put a high-pass filter, so to speak.
The point wouldn’t be to direct it, but to have different mixtures of chemicals (and timings) to mean different things to different organs.
Loose analogy: Suppose that the intended body behaviors (“kidneys do X, heart does Y, brain does Z” for all combinations of X, Y, Z) are latent features, basic chemical substances and timings are components of the input vector, and there are dramatically more intended behaviors than input-vector components. Can we define the behavior-controlling function of organs (distributed across organs) such that, for any intended body behavior, there’s a signal that sets the body into approximately this state?
It seems that yes. The number of almost-orthogonal vectors in d dimensions scales exponentially with d, so we simply need to make the behavior-controlling function sensitive to these almost-orthogonal directions, rather than the chemical-basis vectors. The mappings from the input vector to the output behaviors, for each organ, would then be some complicated mixtures, not a simple “chemical A sets all organs into behavior X”.
This analogy seems flawed in many ways, but I think something directionally-like-this might be happening?
Just because the number of almost-orthogonal vectors in d dimensions scales exponentially with d, doesn’t mean one can choose all those signals independently. We can still only choose d real-valued signals at a time (assuming away the sort of tricks by which one encodes two real numbers in a single real number, which seems unlikely to happen naturally in the body). So “more intended behaviors than input-vector components” just isn’t an option, unless you’re exploiting some kind of low-information-density in the desired behaviors (like e.g. very “sparse activation” of the desired behaviors, or discreteness of the desired behaviors to a limited extent).
The above toy model assumed that we’re picking one signal at a time, and that each such “signal” specifies the intended behavior for all organs simultaneously...
… But you’re right that the underlying assumption there was that the set of possible desired behaviors is discrete (i. e., that X in “kidneys do X” is a discrete variable, not a vector of reals). That might’ve indeed assumed me straight out of the space of reasonable toy models for biological signals, oops.
I had seen recommendations for T3/T4 on twitter to help with low energy, and even purchased some, but haven’t taken it. I hadn’t considered that the thyroid might respond by shrinking, and now think that that’s a worrying intervention! So I’m glad I read this—thank you.
As someone who has Graves’ Disease … one of the reasons that you really don’t want to run your metabolism faster with higher T4 levels is that higher heart rate for an extended period can cause your heart to fail.
More generally: changing the set point of any of these system might cause the failure of some critical component that depends on the old value of the set point,
Gwern gave a list in his Nootropics megapost.
Yup, I’m familiar with that one. The big difference is that I’m backward-chaining, whereas that post forward chains; the hope of backward chaining would be to identify big things which aren’t on peoples’ radar as nootropics (yet).
(Relatedly: if one is following this sort of path, step 1 should be a broad nutrition panel and supplementing anything in short supply, before we get to anything fancier.)
So I find the question underspecified, why do you want this?
Why are you decomposing body signalling without looking at the major sub-regulstort systems? If you want to predict sleep then cortisol, melatonin, etc. is something quite good and this will tell you about stress regulation which effects both endocrine as well as cortisol systems.
If you want to look at nutritional systems then GLP-1 activation is good for average food need whilst grelin is predictive of whether you will feel hungry at specific times.
If you’re looking at brain health then serotonin activation patterns can be really good to check but this is different from how the stomach uses it and it does have the majority of serotonin. But this is like way to simplified especially for the brain.
Different subsystems use the same molecules in different ways, waste not and all that so what are you looking for and why?
Is there a particular reason to not include sex hormones? Some theories suggest that testosterone tracks relative social status. We might expect that high social status → less stress (of the cortisol type) + more metabolic activity. Since it’s used by trans people we have a pretty good idea of what it does to you at high doses (makes you hungry, horny, and angry) but its unclear whether it actually promotes low cortisol-stress and metabolic activity.