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Comment by orangepurple | Hacker News Reader

The bigger story with rapamycin is that the mechanistic target of rapamycin (mTOR) plays an absolutely crucial role in major diseases of modern civilization. One of the ways to inhibit mTOR for free is to simply stop consuming nutrients for extended periods of time.

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As added information: metformin, a common anti-diabetic drug, is a inhibitor of mTOR. It potential adverse effects are less severe than rapamycin but are still significant. Specifically, long term usage can cause renal damage. Its mechanism of action has yet to be fully elucidated.

Can you source this? I believe you and I wanted to look into it. I googled this and I did not find anything explicitly saying renal damage. I did find many articles saying it's not safe to take if you already have renal disease but nothing saying that it causes it.

I even found articles that says it doesn't cause renal failure. I'm sure what you said is some real study just not popularized yet.

Ages ago, I had a colleague who was deeply into hacking of his mTOR pathway. Among other things, this included a permanent calorie deficit and removal of all protein from his diet.

I don't know if he's still alive. Maybe it was working a bit too well, I recall he looked like an extremely tall 13 year old with anorexia.

You can't synthesize some of the amino acids. I wouldn't think such a diet is survivable.

I guess the raw vegetables contain just enough protein to survive

raw vegetables do not contain all amino acids and moreover they cannot be absorbed. You need pulses and sprouted

> ... to simply stop consuming nutrients for extended periods of time

That is not simple for most people.

True but after I went very low-carb, I found fasting to be much easier when it had always been very hard for me previously. I know it's more complicated than "carbs cause hunger pangs ~8 hrs later" but my N=1 experience sure feels that way.

No, there definitely seems to be a "there" there. I went zero carb for 6 months and I was able to continually fast for 24-44 hours at a time, always with zero hunger pangs after the initial "break-in" period, which seems to be about 2-3 weeks. Sadly I don't think the zero carb life is "doable" for me personally, because giving up pasta and pizza is a huge ask. Honestly I would rather die 10 years earlier than live a life with no pizza or carbonara.

simple != easy

Agree; it was very painful initially and not easy. But very simple conceptually!

I did caloric restriction for a year and eased into it gradually until I was eating two small meals a day. I had no ailments but weighed upward of 230 lbs, 104kg. In a year I went down to near zero body fat and weighed 150lbs/68kg. Unfortunately for my build and frame that made me look sickly so I started eating again and Ive settled around 165 and working to put on a little muscle. Overall I'd say I did this whole thing over two years without much effort. Though yes, getting over the hunger pangs is very hard but once over them you quickly learn to ignore them.

Supplementing with potassium, magnesium, and sodium can help alleviate the hunger pangs I've found.

This is Hackernews. The cure is fasting. Whatever disease you have, the cure is fasting.

So many chronic diseases in first world countries these days are downstream consequences of metabolic disorders. That is why it's so commonly recommended.

And somehow the answer to "how did it make you healthier?" is almost always just weight loss or effects related to weight loss.

That is a very shallow perspective. Fasting causes large, measurable phase changes in cellular function (eg autophagy). You can question whether it actually works or not, but there's a very plausible mechanism for why it would work that isn't simply related to calories-in-calories-out weight loss.

I think it's fair to say that we don't have to do something just because there's a plausible mechanism for a benefit. If there are clear and obvious health benefits that are far beyond what you see with a regular calorically restricted diet, I haven't heard them well explained.

https://www.hopkinsmedicine.org/health/wellness-and-preventi....

The points listed there include heart health and the prevention of diabetes and obesity, which are very clearly things traditional caloric restriction also help with. For the other claims I don't see any comparison with traditional caloric restriction (I can't access the source paper).

I think we are talking past each other actually - I read your question "how did it make you healthier?" as in "how did it act to make you healthier?" and now I think you were saying "how did you determine it made you healthier?". Ambiguity of English strikes again...

Just like you wouldn't grasp the incredibility of an acid trip unless you did one yourself.

Changes in one's perception of local stimuli and focus abilities are almost impossible to convey to others.

If you want to sell me on the health effects you should be able to list them. If it made you feel better but not in an objectively measurable way that's great, but that's not a health effect.

My main point was that fasting could supplement or partially replace rapamycin the drug

If that's the mechanism by which the anti-aging effect takes place that would be promising for a lot of things, because many things, including Caffeine, exercise, and traditional caloric restriction inhibits mTOR, so there's lots of options, but as the person I originally responded to pointed out, for some reason Hacker News will always choose fasting.

It’s simple, but not easy. Intermittent fasting is an easier way to start compared to traditional fasting. Imo it’s still better than other diets due to its simplicity.

I think they meant fasting.

> One of the ways to inhibit mTOR for free to simply stop consuming nutrients for extended periods of time.

What is an extended period of time in this context? I happen to consume all my meals within seven hours every day and only drink water in between. Would that help?

(Not doing this for health reasons, it is just a habit.)

This [1] study was pretty thorough on different fasting lengths. They tested 1422 patients for fasting lengths between 4 and 21 days, with a maximum calorie consumption of 200-250kcal and a moderate-intensity lifestyle program.

It concludes that all fasting lengths are beneficial, and are likely going to result in a) reduction in weight and waist circumference, b) beneficial effects on blood lipids, regulation of sugar and other blood-related parameters, including lower blood sugars and higher ketone body levels, c) an increase in physical and emotional well-being and absence of hunger, d) a high probability of decrease of pre-existing health-complaints, e) very limited chance of side-effects.

[1] https://journals.plos.org/plosone/article?id=10.1371/journal...

To build on this post it is further beneficial to understand the importance of the interaction between clock genes and nutrient intake timing for optimal results

https://podcastnotes.org/high-intensity-health/attia-7/

Around day 3 or day 4 of a water-only fast or (the potentially easier but still effective option of) of a fasting-mimicking diet fast.

A good measure is whether or not you feel that empty, churning feeling in your stomach. Another good measure is if you're into the idea of eating something like plain cabbage or oats.

I feel that after a few hours of not eating. Is feeling it or not feeling it the sign that I've reached the necessary effect?

I have no personal experience with this, so I must have read I somewhere. Usually in the first hours your get hungry, which eases off after some time. After that, you can until you are hungry again.

I think it is bare minimum for good clean digestion. As far as ALL the benefits of fasting... I think it is a good start.

Not an expert by any means, but based on some sparse reading I'd guess it's in the "few days" range, not a few hours.

> ways to inhibit mTOR for free to simply stop consuming nutrients for extended periods of time

How frequently and for how long must one fast to see this?

As long as you can bear it. Which for me has been 24 +/- 4 hours between meals for 9 months and counting.

> long as you can bear it

This gives zero evidence a threshold has been reached for enzyme activation.

There is evidence of effects after 72 hours of fasting [1]. But we also know of counter-effects around 24 hours, when glucose released by the liver breaking down amino acids from muscle wasting (EDIT: autophagy) partially reactivates mTOR [2]. It could be massive or minimal benefits through 24 hours, we don't know, benefits which reduce between 24 hours and some other number, and then increase until, or until right before or well through 72 hours.

[1] https://journals.plos.org/plosone/article?id=10.1371/journal...

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390257/?_escap...

I wouldn't call protein breakdown in the muscle "wasting" without additional effects

> wouldn't call protein breakdown in the muscle "wasting" without additional effects

Fair enough, given it's voluntary [1]. It's biologically identical to wasting, however.

[1] https://en.wikipedia.org/wiki/Wasting

There's some evidence that exercising during the fast helps minimize the loss of muscle.

> some evidence that exercising during the fast helps minimize the loss of muscle

The original point was autophagy reactivates mTOR. This isn’t a linear system. It could be that a 20-hour fast downregulates mTOR more than a 30-hour fast. (We know it works at 72 hours.)

And what conditions did you cure with this regime?

Did your overall calorie intake remain the same?

Benign tumors on my skin disappeared and I lost 80 pounds

Benign tumors? Moles?

What is your current height and weight? If I were to lose 80lbs I would become emaciated.

And if I lost 80lbs I would be on the low-side of "normal weight" by BMI.

https://c.tenor.com/rI48-HMbEaMAAAAC/spaceballs-lost.gif

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