#141

I know this thread is old, but I’m new here. I am also on 2mg with grapefruit juice per week. I get very low hrv readings for the night following the dose, way below my average, also raised rhr.

Screenshot_20241202_173642_WHOOP

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#142

It seems that the reduction in HRV seen with rapamycin may be very similar to the reduction seen in HRV from 48 hour + long Fasting intervals… its good for the body, but does put some stress on it.

See this paper:

Effects of a 48-h fast on heart rate variability and cortisol levels in healthy female subjects

Background/objectives:

The physiological changes that occur during fasting are not completely understood, regardless of the cause for fasting (for example, medical, lifestyle, religious, political or famine). The purpose of this study was to examine the effects of a 48-h fast on heart rate variability (HRV) and cortisol levels in healthy young female volunteers.

Subjects/methods:

A total of 16 young healthy female volunteers underwent 48 h of total fasting under 24-h medical surveillance. Psychological (subjective feeling of hunger) as well as physiological data (HRV, diurnal cortisol profiles) were measured upon admission (Day 1), and after 24 (Day 2) and 48 h (Day 3) of fasting.

Results:

There was a measured weight loss from Day 1 to Day 3 that resulted in significant body mass index (BMI) reduction across all subjects (P<0.001). The slope of the diurnal cortisol profile significantly shifted towards lower values from baseline to the end of experiment (P=0.002). HRV during resting showed a significant (P<.001) decrease in standard deviation of the normal-to-normal interval (SDNN) and root mean square of successive differences (RMSSDs) from Day 1 to Day 3 of the experiment, with a small increase after 24 h that did not reach statistical significance. A 48 h of fasting also induced a significant (P<.001) decrease of mean interbeat intervals (IBIs), SDNN, RMSSD and log high-frequency (HF) power during head-up tilt testing.

Conclusions:

An acute (48 h) total fast induced parasympathetic withdrawal with simultaneous sympathetic activation. These changes appear to reflect stress. Further studies are needed to demonstrate the specificity of these changes to fasting.

Paper:

https://www.nature.com/articles/ejcn201332

Full PDF of Paper Attached:

mazurak2013.pdf (547.0 KB)

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Bryan Johnson stops rapamycin
#143

I don’t think there’s any evidence that 48h+ fasts are “good for the body” (beyond mere calorie restriction).

#144

I would disagree - It think its well known that autophagy ramps up after 48 hours of fasting. Rapamycin doses (at some dosing levels) seems to be very similar in its effects to a significant multi-day fast.

References:

How long do you need to fast for autophagy?

Depending on the individual’s metabolism, significant autophagy may take two to four days of fasting in humans. Autophagy is believed to begin when glucose and insulin levels drop considerably. Animal studies have shown evidence of autophagy after 24 hours of fasting, which starts peaking at around 48 hours of fasting.

Extended fasting

Extended fasting involves abstaining from food for prolonged periods, typically 24 hours to several days. This can trigger a moderate autophagic response, where the body starts using autophagy for energy and cellular repair.

Longer fasts, exceeding 48 hours, may be needed for a more sustained response, promoting the breakdown of damaged cellular components and potentially improving overall cellular health.

Calorie restriction (CR)

Reducing your daily calorie intake by 10–40% can trigger autophagy. This aligns with the concept of an “autophagy diet,” where consistently eating less over 3–15 years increases the activity of genes and molecules involved in cellular cleanup. [4,5]

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#145

That’s a potential mechanistic explanation of why it could be good. But as of today there’s zero evidence that’s it is actually good in humans (again, beyond mere calorie restriction). The scant evidence we have actually points to the other direction: 8-hour time-restricted eating linked to a 91% higher risk of cardiovascular death | American Heart Association

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#146

So - you’re saying there is no evidence that autophagy is beneficial for organisms?

Benefits of Autophagy

Autophagy has important effects that occur both within and outside of a cell.

Within the cell, autophagy can help:4

  • Decrease oxidative stress (damage to cells caused by unstable molecules known as free radicals)
  • Keep DNA and genes stable
  • Avoid the premature deterioration and aging of cells
  • Improve conversion of nutrients into energy
  • Improve the elimination of waste
  • Eliminate pathogens and other foreign materials within cells
  • Prevent tumor formation by eliminating toxic substances

Outside of the cell, autophagy can help:

  • Decrease inflammation1
  • Improve the transmission of nerve signals in the brain5
  • Keep the immune system functioning normally6

Yin Z, Pascual C, Klionsky DJ. Autophagy: machinery and regulation. Microb Cell. 2016;3(12):588-596. doi:10.15698/mic2016.12.546

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#147

No, I didn’t say that. I said that there is no evidence that long-term fast (48h+) is good (beyond mere calorie restriction). Period. Yes it activates autophagy, but it does other things. And overall, there’s no evidence that it’s good (unfortunately). Despite the autophagy. (And again, beyond CR.)

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#148

I would say that that fasting (48 hours+) is just one example of caloric restriction (that evolution has strongly adapted for to survive times of scarcity), and the benefits are well-proven (in fact the best proven of any longevity approach).

But - I can also admit that I don’t have the research in front of me that definitively proves that 48hour + fasting is identical to caloric restriction in these effects. There is a lot of discussion in the research community as to what exactly can be categorized as “caloric restriction”; is it a reduction from ad lib eating (of lab animals), or eating at the same level as wild-type in nature, etc.

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#149

I think that 48h+ fasting might actually be worse than “normal” calorie restriction. So for instance if you fast 2 days per week you should compare that to someone who eats the same diet every day but eat 29% less (2/7).

I looked at that 2 years ago and I remember that:

  1. Animals that do IF don’t live longer than those that do normal CR.
  2. Humans who practice IF don’t live longer.
  3. There are no more people doing IF among centenarians than among the general population.
  4. RCTs on IF vs CR don’t conclude that IF is superior.

If all the above points were true, then yes, we could say that IF is good. Evidence is not there.

(And even calorie restriction has its limits and can be bad btw.)

#150

I think part of the issue / problem with the Intermittent Fasting (IF) data is that there are many different interpretations and definitions of IF.

You mention that " 1. Animals that do IF don’t live longer than those that do normal CR."

which I suspect is true, but if you can achieve lifespan and healthspan extension anything close to 40% CR with a mimetic like rapamycin (without the pain and suffering of CR) then most people would agree that its a great accomplishment.

You mention: “Humans who practice IF don’t live longer.”

  • probably true, but the data is very spotty, and the definition of “IF” is again an issue. What level of autophagy are they stimulating in their version of IF?

You mention “There are no more people doing IF among centenarians than among the general population.”

And how do they define IF in these studies? I doubt its 2+ days of fasting every week, for decades. So the data is not comparable to rapamycin dosing. And, the centenarian data is famously pretty sparse and of low quality (especially when it comes to diet and fasting over the past 50 years of their lives)

You say: “RCTs on IF vs CR don’t conclude that IF is superior.”

Perhaps that is true, but again, if I can get even close to CR with a weekly rapamycin tablet without the pain and suffering of CR or IF, I’m happy.

Short term IF (i.e. 16 hours not eating, 8 hour window of eating) will not induce autophagy to any significant effect I suspect, and thus not provide the benefits.

And the CR that is typically studies in animals is much higher (ie. greater reduction in calories, typically 25% to 40% reductions from Ad lib diet) than the caloric restriction done in IF that is seen in human applications. So - apples and oranges in their comparison.

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#151

Wouldn’t you think that somebody overweight (BMI>24) fasts 2 days then they live longer and somebody underweight (BMI<18) fasts 2 days they live shorter? In between we don’t know, it may depend on activity level.

#152

Why are you talking about rapamycin? Our discussion was just about 48h+ fasts: Rapamycin and Impact on heart rate and HRV? - #143 by adssx Rapamycin is unrelated.

I just maintain that, as of today and as of now, there are no benefits of long fasts beyond calorie restriction, and they could even be detrimental.

Yes, there are different forms of IF, but the conclusion still stands for most forms: the main benefit (if
any) seems to come from calorie restriction.

If I go around this forum and tell people to “eat according to the moon” because it’s super healthy and not eating on full moons, new moons, third quarters, and first quarters (so basically one day per week of fast :stuck_out_tongue: ) activates autophagy: it would be somehow true. But you’d tell me it’s intellectually dishonest and misleading. Because the only benefits come from calorie restriction. And not from the phase of the moon. The same reasoning applies to long and/or regular fasts (as far as I know and until proven otherwise).

#153

In a 48 hours fast you have a lot of confounding factors, like for example sodium consumption ceasing within that window. I wonder if you’d have to control for all of these except calories to know whether it is the restriction of calories. But then it might be glycogen stores or something to do with ketones. So how do we know it’s autophagy (I don’t know how important this is) or some other thing?

But it might be a good idea to look at times when HR increases or HRV decreases and when that’s a good thing and compare with such an increase from rapamycin. To try and figure out why. Worst case you can compare the expected lifespan benefit from rapamycin vs. the reduction from the side effects.

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#154

Actually answers are in this paper: Dietary restriction impacts health and lifespan of genetically diverse mice

  1. IF (one or two days per week) is significantly inferior to calorie restriction in terms of lifespan extension
  2. 20–40% CR can be detrimental (especially in terms of immunity)
  3. The effects are highly individualized based on genetics
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#155

Could be this, also how some become euphoric from Rapamycin. :joy:
It also makes sense why some get anxious from rapamycin, or even feel better.

Further, acute low (1.5 mg) and medium (2.25 mg) EVR administration increased state anxiety levels accompanied by significantly elevated noradrenaline (NA) concentrations. In contrast, high‐dose EVR significantly reduced plasma and saliva cortisol as well as NA levels and perceived state anxiety.

In conclusion, the present results provide evidence that an acute oral exposure of EVR dose‐dependently mediates a potent inhibition of T cell proliferation, IL‐10 suppression, altered systemic levels of neuroendocrine hormones (i.e., cortisol and NA), and changes in state anxiety in healthy probands. Furthermore, independent of the dosage, EVR seems to induce subjectively perceived side effects only in a minimal extent.

However mTOR inhibition also has been linked to depressive and anxiety‐like behavior in rodents and the induction of euphoria followed by melancholy, mimicking biopolar disorder in patients with breast cancer. 24 , 25 , 26 , 27

Noradrenaline:

In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility.

So (?):

Rapamycin → Increased Noradrenaline → Increased HR, blood glucose, anxiety, euphoria, depression
Rapamycin → PCSK9 → Increased blood lipids

Inhibiting mTOR maybe mimics “you’re starving! get some food!”, so rapamycin is just using something the body already have but in a different way? Which would limit I believe any mTOR inhibitors effect on lifespan? Or super refined or in combination with other treatments?

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Dose-dependent effects of rapa on anxiety?
#156

My whole point of posting this paper above (Effects of a 48-h fast on heart rate variability and cortisol levels in healthy female subjects | European Journal of Clinical Nutrition) was because I was researching the issue of reductions in HRV seen with rapamycin and I was trying to understand is this a situation / side effect unique to rapamycin or is it something typically seen when any mammal is deprived of nutrients (either by reducing food, or via a caloric restriction mimetic) for a significant period of time. Ongoing caloric restriction doesn’t really emulate the weekly dosing approach that most of us do with rapamycin, thus I started looking at 48 hour fasting as a most directly comparable scenario to look at the HRV impact seen with rapamycin (by some people).

I’m not really interested in IF per se. And I totally agree with you - IF by whatever approach may not have any beneficial effects over and above the caloric restriction. I’m not really arguing against that position.

The point that this research paper seems to be making is that, at least if we look at HRV impact of rapamycin, it seems that from a caloric restriction point of view rapamycin at the dose we typically see in longevity applications is acting similar to a fast of a few days. Obviously dose/response relationships will still be in effect.

Additionally, it seems that this is important because in my mind this negates the rationale that Bryan Johnson used as one of his reasons for dropping rapamycin: Bryan Johnson stops rapamycin

It would be like stopping caloric restriction (if you were following that protocol) because it did the same thing, even though we know it improves lifespan and healthspan in most situations.

Anyway - I don’t think we’re in disagreement generally on these points. My focus was never on IF, but rather I was using it as the most convenient example of how caloric restriction for a few days has the same effect on the body as rapamycin, and while it may be a bit of stress on the body, I suspect that overall the positives outweigh the negatives as proven by the mammalian rapamycin longevity studies.

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#157

Understood and agreed! Bryan Johnson’s reasoning is weird. (And I say that as someone not taking rapa.)

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#158

I love this rule! Every religion or cult needs some sort of nonsensical and painful complication to feel legitimate and to enhance a placebo effect.

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#159

If you’re talking about mouse studies, where mice fast every other day, that’s not equivalent to IF in humans. That’s pretty extreme in particular considering that a day for a mouse is more like a week for a human. If you want to see the effect fasting for a day or two you need to look at something more equivalent. Studies on calorie restriction in mice are exactly that. Calorie restricted mice usually get fed once a day and because they are very hungry on the low calories, they tend to eat most of their food quickly, instead of nibbling on it throughout the day like ad libidum fed mice. So they actually get a period of fasting for over half a day. That, for a mouse, is likely equivalent to a day or two for a human. If that were harmful for the mice, they wouldn’t be living longer.

Here is a quote on this:

"In contrast to mice in the TR condition which had unlimited amount of food for only 12h each day, the CR mice had a restricted amount of food that was available for the full 24h. Compared to TR, CR had a stronger impact on mouse behavior (Figures 2M–T). The CR mice shorten their feeding time, regardless of when (day or night) the food is made available (Figures 2M, 2O, 2Q 2S, S4D and S4E), thereby self-imposing a temporal restriction of food intake to 2h daily even though they have 24h of food access. "

Source: Mice Under Caloric Restriction Self-Impose a Temporal Restriction of Food Intake as Revealed by an Automated Feeder System - PMC

In fact, I recall some mouse study that showed that calorie restriction only worked when the mice were allowed to eat the food quickly while fasting rest of the day, but not when the food was distributed throughout the day. I can’t be bothered to look for it. Maybe someone knows what study I’m referring to.

We don’t really have data on whether they live longer or not. I don’t think we have long term data on people that deliberately fast intermittently. Observational studies on people that fast intermittently probably represent people that happen to lack a regular eating schedule and we know that not having a regular schedule is bad for life span, regardless of how the schedule is.

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#160

I’ve been tracking HRV daily for 5 years on a spreadsheet and there is zero correlation with rapamycin
There is a strong correlation with cRP - a measure of inflammation. When my cRP was >10 my HRV was 8 ms
Now it is < 0.5 and HRV is > 70 ms
r squared is 0.7
There have been many factors influencing inflammation:
exercise - especially HIIT
diet
sleep - especially deep sleep length
Stress is no doubt important too but hard to quantify
Supplements - Omega 3, curcumin, LDN have the largest effect

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