There’s a good part and a bad part to this. The good part is, that here’s an occasion to use Wolfgang Pauli’s excellent observation “this is not even wrong”. The bad part, is of course that the model used here is so catastrophically misaligned that it needs wholesale discarding.
You asked if someone here has been on CR - I’ve been interested in CR since the 80’s when Walford’s first diet book came out, and I went on CR for a number of years, successfully, before quitting for social and other reasons, which I’ve explained elsewhere on this site. I had no difficulty maintaining CR insofar as hunger.
More relevantly, there was a long time CR related list (even before the crsociety website existed), on which I was an active participant, where the participants shared a ton of research and which generated a lot of ideas and approaches. And what you are proposing fits right in with one of the biggest and long running discussions, the so called “Hunger Hypothesis”.
The Hunger Hypothesis, is the idea that the very thing that you are seeking to abolish, in order to make cutting calories, and thus practicing CR easier, is the thing that makes the benefits of CR possible.
Note that what you are doing is very risky from a scientific method point of view. You are ignoring the “black box” model and engaging in mechanistic speculation which almost always results in incorrect ideas of how things work, especially in biology. The black box approach is to look at inputs into the black box, and observe the outputs out of the black box and ignore (at least temporarily) what happens inside the black box. We can say this: based on animal studies cutting calories [input] results in longer life [output]. But you can’t now suddenly change the input and expect the same output, based on speculation of what happens inside the black box. Speculating on what happens inside the black box is the essence of mechanistic speculation.
What we observed: mice/rat/animal model given fewer calories resulted in - a longer life. Now you are changing the input, and you expect mice/rats/animal model given fewer calories, and with their appetite suppressed will result in - a longer life(??). Nope. This is not the same - the inputs have changed. Once you change the inputs, you must run the experiment again, to see if you get the same output. You speculated mechanistically that changing that aspect of the input (appetite suppression) is irrelevant to the inside of the black box, and you’ll get the same output. But you have no way of knowing if your speculation as to what the black box does (“it ignores appetite suppression”) is correct - that’s speculation. To know, you must observe - not assume - the outcome.
How CR works is part of what happens inside the black box. We have all sorts of ideas. And appetite - the sense of hunger with lower calories - is an integral part of the CR effect, because that is how the body operates signalling pathways. Part of the benefits of CR is hormetic, and a whole cascade of processes, the body senses there are not enough calories, so it uses them more efficiently, re-uses faulty cell components through autophagy, it rallies the body defence mechanisms to survive the caloric deficit, it sharpens the functionality of multiple systems - energy output, neurological efficiency, sense acuity - in order to allow the animal to find food. And how does all of it start? With the first step - signalling. The body must know that it is in a calorie deficit. One way it knows, is through sensing hunger - hunger is a signal in the body that there are not enough calories. This has consequences - there is a whole cascade of hormonal signals, gherlin and neuropeptide Y among them, that are feedback mechanisms with hunger.
To just look at neuropeptide Y - first, what it is, courtesy of our AI overlords - I’m using AI instead of chasing papers that I’ve explored decades ago, during the original discussion of the hunger hypothesis, as it’s faster:
"Neuropeptide Y (NPY) is a 36-amino-acid peptide that plays a role in many physiological and homeostatic processes in the nervous system:
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Appetite regulation: NPY is a key regulator of appetite, stimulating food intake. NPY levels increase during fasting and exercise.
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Stress and emotional behaviors: NPY is involved in regulating stress, anxiety, fear, and other emotional behaviors.
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Energy metabolism: NPY regulates energy metabolism.
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Immune system communication: NPY is a critical transmitter between the nervous system and immune system.
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Blood pressure: NPY plays a role in controlling blood pressure.
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Other physiological processes: NPY is involved in other physiological processes, such as learning and memory.
NPY is found in the central nervous system (CNS), sympathetic ganglia, and extra-neuronal tissues like the lung urinary tract, spleen, blood vessels, and reproductive organs"
Neuropeptide Y is elevated in hunger:
"Yes, neuropeptide Y (NPY) is considered elevated when someone is experiencing hunger, as it is a potent neurotransmitter in the brain that stimulates appetite and food intake, essentially signaling the body to eat when energy stores are low; its levels tend to rise during fasting or when experiencing calorie deficit.
Key points about NPY and hunger:
NPY primarily acts in the hypothalamus, a region of the brain that regulates appetite, and when activated, it triggers a strong urge to eat by increasing meal size and decreasing the feeling of satiety.
- Regulation by energy status:
When energy levels are low (like during fasting), the production of NPY increases, leading to increased hunger signals.
- Opposite effect of leptin:
Leptin, a hormone released by fat cells, acts as a satiety signal and can suppress the release of NPY."
_Neuropeptide Y is neuroprotective:
" Yes, neuropeptide Y (NPY) has neuroprotective properties:
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Reduces neuroinflammation: NPY can reduce neuroinflammation.
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Increases BDNF levels: NPY can increase the levels of BDNF and NGF.
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Stimulates autophagy: NPY can stimulate autophagy.
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Reduces oxidative stress: NPY can reduce oxidative stress and mitochondrial dysfunction.
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Decreases glutamate-induced excitotoxicity: NPY can decrease glutamate-induced excitotoxicity.
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Mitigates endoplasmic reticulum stress: NPY can mitigate endoplasmic reticulum stress-induced neuronal cell death.
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Inhibits caspase-3 and caspase-4 activities: NPY can inhibit caspase-3 and caspase-4 activities.
NPY is a neurotransmitter or neuromodulator that plays a role in regulating physiological processes. NPY levels are altered in some neurodegenerative and neuroimmune disorders. NPY’s neuroprotective properties are mediated through the activation of Y1, Y2, and/or Y5 receptors."
And that’s just neuropeptide Y. There are so many others - all you have to do is look at the fasted state and the dramatically different signalling pathways activated as a result of this state.
Now you are proposing to not inform the body that it is in a state of caloric deficit. You are essentially, through chemical means, stopping the signalling pathway of hunger. Guess what. You are not going to experience the same results. It’s like not knowing how much you have in your bank account [how many calories]. If you do know, and are approaching zero funds, you are sent an alert [experience hunger], so you can now take actions [CR benefits] hoping to make more money, get a job [energy output], get an education, cut expenses [autophagy]. If someone stopped you getting the alert (hunger), you will lose your money (cut calories), but you will not know to get a job, an education or cut expenses, and you’ll just go bankrupt, no benefit of CR, instead harm. CR without hunger may be not only not beneficial, but harmful.
Here is an interesting fact - the signalling pathways are so powerful that they can abolish benefits of CR. How do we know that? Because we have hints of it in studies showing that in f.ex. fruit flies, merely sensing that food is around, abolishes most CR benefits. They don’t even need to eat more to abolish CR benefits - all they have to do is sense that food is around:
When you make a massive intervention like GLP-1RA agonists or some agents that suppress appetite, you are really messing around with the physiology of the body. There are consequences to that. You cannot get away with changing the inputs and expect the same output.
I therefore have to say, you must completely re-think your approach to science to account for the black box model in situations where we don’t fully know how a drug or intervention (like CR) work. Any - any - change in the intial conditions must be tested for outcomes. You cannot assume anything.
