I’ve been trying to come to a better understanding of fasting for autophagy for a week or so. Part of that is refreshing everything I’ve read while some time is looking for new insights. Like many of us, I have some extra “lean body mass” that I wouldn’t mind losing - excess skin. (Which is why I don’t get upset if my body composition scale tells me I’ve lost some LBM. I’d love to.)
I know Jason Fung has said his patients don’t usually need some skin removed after losing lots of weight and my recollection is he doesn’t say it’s known to be autophagy because (I believe) it hasn’t been medically proven.
I’ve read a handful of older posts here but nobody really talking about success with ensuring they don’t have too much loose skin. Maybe my search engine skills aren’t at the “Master level”, but I get no ideas of how long to fast at a time or how many months or years of regular fasting it takes. For the last six weeks, I’ve been fasting either every other day, 3x/week, or a longer one (about 65 hours) followed two days later with an over night (40-ish) hours.
Everyone seems to say longer fasts are better, but (somewhere) I saw the idea that the rate peaks around the 36 to 48 hour mark.
I guess I’ll cut it there. I’m looking for some clarity, or good sources to study. Anybody’s experiences with seeming to reduce loose skin would be interesting, too.
My sister has found Dr. Fung’s book, The Obesity Code, to be quite helpful. My understanding is that a lot of what you want to know is covered in the book.
Except for a single 20-pound (9 kg) whoosh, the fat loss I experienced was slow enough for my skin to stay tight. I can no longer find the pictures of him on line, but Dr. Fung had a patient with a great deal of loose skin (it was creepy-looking, as well as crepey-looking), who apparently tightened it all up by fasting. The before and after photos were remarkable. A couple of women have posted such before and after pictures on this site, but I wouldn’t know how to go about finding them, sorry.
Because my ketones are so low now, however, I’m not sure this is really true. I have to assume that if I fast 32 hours, then exercise, then make it another 3 hours before eating (total of around 36 hours), I’d be in a state of autophagy, even though my GKI is higher than many people at this stage. (BHB around 0.1-0.2 every morning, and fasting helps but doesn’t create much increase.)
Bob, in a mouse autophagy is still increasing after 2 days of fasting. That’s where some of the stuff about those hour figures comes from. At that point, the mouse is halfway or more to death from starvation; a similar time for a human would be a month or several months.
Loosing excess skin while fasting is a very individual thing. Some people end up with almost no loose skin at all, while others on the same fasting regimen seem to not lose any…
(Other) Bob – this is the mice thing again, and mice have vastly faster metabolisms than people. Humans are far slower with digestion and the chemical changes which start/increase autophagy.
Autophagy was found to be still increasing in some mouse tissues after 48 hours of fasting. The mouse is way down the road to death at that point, while people are really just getting into a really ‘depleted’ state, as with glycogen.
The later mention of “you will achieve peak levels of autophagy around Day 4 and 5…” is certainly closer to the mark, but again I really question that analysis. Insulin keeps declining and glucagon keeps rising past 4 or 5 days when people are fasting, and the picture for autophagy with mTOR and AMPK keeps getting more favorable too. I don’t claim to know when the peak for human autophagy would occur, and it would have to be tissue-specific, to begin with, but to this point I’ve yet to see a good analysis why autophagy would slow after a certain time (barring death or something ).
GKI for rating autophagy - I think it loses meaning for people who aren’t eating substantial amounts of carbohydrates. People on a ketogenic diet can be chowing down on all sorts of meat, for example, and still have relatively low glucose to ketone ratios.
If somebody’s coming off a ‘standard western diet’ then it makes more sense, i.e.there will be a meaningful and substantial shift in the ratios there.
I think excess skin that simply won’t leave (I am of that tribe) can sometimes be attributed to many years of yo-yo dieting, gaining and losing. Skin can be like a beloved old pair or elastic waist sweat pants… after so many years it simply loses elasticity. I have less extra skin than I have when losing weight on other diets, so I do believe there is something about keto that helps in that area. But the older you are (also my tribe) and the more you’ve stretched out your skin repeatedly, this may just be the consequences. I’m okay with that. I rarely feel the need run around naked any more… since I also gave up booze.
Doug, thank you for starting this thread. I was thinking of starting a few threads each with a similar title and premise. What is the best amount of time to fast for 1) weight loss 2) insulin sensitivity 3) replenishing your immune system 4) autophagy. I think a post with everything we have on each one could be useful. I have read everything I could find on this topic, and feel I have a weak grasp of the truth behind the mechanisms, but I will nonetheless, give my thoughts on this topic.
My understanding is that autophagy happens whenever we have not eaten protein for a while (hours). The extent of autophagy starts as a miniscule amount, but starts to ramp up after 12-16 hours. Autophagy continues to ramp up until (I believe) as Bob mentioned, your GKI ratio falls below one provided you have not eaten any (even small) amounts of proteins. I appreciate your thoughts and concur that 2 days for a mouse is much longer than 3-4 days for a human, but perhaps the issue is relative time in catabolic state (and I have zero knowledge on mice and the transition from anabolic to catabolic). After 3-4 days for metabolically healthy (human) individuals have the GKI ratio falling to around 1. I suspect that the suggestion of 3-4 days is for this reason. Now, being metabolically unhealthy, it takes me more than 4 days to reach a GKI under one. Since there is a range to get there for people, this makes it more challenging. You might find this paper interesting, since they talk about more than just mice for autophagy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835977/ .
Part of the reason you may have read that it decreases after 4-5 days hours is due to the number of autophagosomes, which I ready (somewhere sometime) seemed to decrease after 120 hours in most humans. I think that is irrelevant without more information. If a very healthy person with little degraded protein strands were to fast, they BETTER not have as many autophagosomes ready for dissolution as my decrepit body if we fasted for the same time. A number of damaged cells does not equate to the body’s desire to find degraded proteins (imho). The more damage, the easier/faster it is for the body to at first surround and then digest the errant protein - giving more autophagosomes, once the “quick and easy to find” proteins and found, after digestion, the number of autophagosomes decreases, but I suspect the body’s desire to search for damaged proteins increases as the body wishes to create new better working replacements “once it feasts”. I have not found any studies that have looked at extended fasting and autophagy outside of measuring autophagosomes, which again, I think it as useful as measuring blood sugar to diagnosis early metabolic disease.
Since the GKI ratio stays between 0.5-1 (ish) once you get to this point, IF, there is a connection between autophagy and GKI, it is when this ratio becomes static that I would presume you have “just” reached the maximum autophagy, and that this would continue until you eat protein. If a person fasts for 365 days, they would therefore have some growing autophagy for 5ish days, and then 360 more days of maximum autophagy (whereby anything found is identified for clearance/re-assimilation).
(Michael - When reality fails to meet expectations, the problem is not reality.)
Bob, thanks for the link. I find this somewhat confusing:
Two reasons why people fast are to lose fat and improve their mental clarity. In order to do either of those things, the body needs to reach a state of autophagy — your body’s natural method of detoxification…
I thought fasting induces ketosis. It’s ketosis that utilizes stored fat for energy and provides the ketones to the brain that results in mental clarity. I thought ‘autophagy’ is just a byproduct of lower protein consumption. The body’s way to recycle amino acids and/or dump the unusable debris. The article seems to imply that autophagy is a metabolic state. I’m not playing word games. I think it’s important to understand stuff. One can certainly be in ketosis but not autophagy. But can one be in autophagy but not ketosis? Healthy autophagy? I doubt it.
Autophagy happens when your body recycles and gets rid of old or excess cells (like fat) that don’t serve a purpose or benefit your health.
What exactly are ‘old or excess cells (like fat)’ that don’t serve a purpose? Fat cells certainly serve a purpose and were stored specifically to serve that purpose when you fast. Even ‘excess’ amino acids and/or protein can be utilized for energy if needed.
The GKI stuff simply reinforces the fact that ketosis is the metabolic state in which autophagy can occur. Not vice versa. But even then, ketosis is not necessary. You can certainly force autophagy if you keep your protein intake sufficiently low enough with or without ketosis. That, in fact, is one of the primary concerns about aging - loss of lean mass. Even folks eating SAD can accomplish it if they try. Eat just fruit and veggies for a few months and see just how much lean mass you lose. Unhealthily skinny vegetarians and vegans got that way doing so.
This is not to say that I think autophagy is nonsense. Just that I think it’s important to keep things in their right perspective.
Autophagy, being a catabolic process, is facilitated when the body is in a primarily catabolic state, meaning the insulin/glucagon ratio is low. This state is largely controlled by carbohydrate intake, since high serum glucose (carbohydrates being glucose molecules arranged in various ways), calls for insulin to be secreted to get it out of the blood stream where it causes damage. At the same time, glucagon secretion is inhibited, since glucagon is the primary regulator of gluconeogenesis, and the body has no need to be making even more glucose when serum glucose is already high. Thus the insulin/glucagon ratio rises, and the body becomes primarily anabolic.
Since proteins all have a lifespan, ranging from a few minutes to several years, there is always some amount of autophagy going on, even when the metabolism is primarily anabolic; just as there is always some tissue growth and rebuilding going on, even when the body is primarily catabolic. However, fasting, which leads to a low insulin/glucagon ratio and is therefore primarily a catabolic state, is one of the ways to promote autophagy. Interestingly, nutritional ketosis is also a primarily catabolic state, and one researcher has described it as a similar state to fasting, but without the hunger.
My understanding is that it is more an ongoing process, one that is encouraged or inhibited whenever catabolic or anabolic processes, respectively, are predominating at the time. Autophagy is the breakdown (catabolism) of proteins that either have been damaged or have reached the end of their useful lives, so it has to be occurring at some rate all the time, though fasting and nutritional ketosis are states in which it is greatly encouraged. We tend to forget, I think, that we are supposed to be alternating between anabolism and catabolism to some degree throughout the day. While I tend to see everything through the lens of insulin level, I do have to admit that there is also some degree of anabolism going on all the time, as well. This we know from the fact that there are a few other anabolic hormones, in addition to insulin.
I can understand/accept that some level of autophagy may be ongoing in the metabolically healthy, but there’s the often reported idea that MTOR inhibits autophagy, and since that cycle is protein sensitive, that’s why protein should be avoided while fasting more than just some fat calories or a gram or two of carbs (in the day).
In all these studies, it’s important to discern the metabolic circumstances under which the observations were made. I don’t want to automatically claim that everything is different on keto, but we do know that some things are. My hunch is that we need more research done on people who have been on a ketogenic diet for a number of years, before we will know just exactly how the body handles protein under such circumstances. From some things Bikman has said in recent interviews, I get the impression that recent research has uncovered a more nuanced view of just how protein and mTOR interact.
Michael, @CFLBob gets the credit for the thread. It really is a good subject.
For weight loss - I think it’s an individual thing, to a huge extent (originally, no pun intended but I had to laugh). For some of us, ketogenic eating brings metabolic healing, and fasting is what makes for fat loss. For others, it’s not so and/or fasting is unpleasant or has other bad consequences. There’s definitely as aspect of finding one’s own way, there.
Insulin sensitivity - I don’t know if there’s a ‘point of diminishing returns’ in that during a very long fast, insulin has dropped to a low level and remains there. Perhaps not a true ‘constant,’ and I would think that the ‘dawn phenomenon,’ and other things bring some variance, but the average insulin level is usually much lower than when eating normally - if the normal diet has substantial carbohydrates in it.
I do accept that the amount of time we spend eating extremely low-carb or outright fasting helps, if insulin resistance is a problem. It can take months/years before the full benefits of keto eating present themselves to an individual, and likewise I’d say that “a lot” of fasting (whether cyclically and shorter-term, or fewer but longer fasts) is better than “a little.”
Immune system reset and regeneration - I don’t know about this one. It certainly sounds great, though. I do think that changing things once in a while is often good, as with giving the liver a rest from processing food. If it indeed does take 3 to 5 days to recycle immune cells, then from my point of view all is well - I see the 3rd day as when the gastrointestinal tract is empty enough that, “Okay, now we’re really fasting…” That said, fasting that many days is really hard for some people.
If the number of autophagosomes goes down after 5 days fasting, then that would be a good item of data, IMO. To this point I’ve not seen anything about it for humans. I think it’s a real question how the body goes about things when truly ‘fasted.’ To what extent does it go after the ‘bad stuff’ versus skin cells, for example.
It may be that having a comparatively large amount of faulty protein structures that need recycling doesn’t make for faster, more aggressive recycling. The conditions, like high insulin and higher blood sugar, that cause problems, can also slow down and hamper the body’s attempts at fixing the problems. It’s too bad that there is such a lack of studies about this stuff on humans.
I agree - and Alzheimer’s Disease, etc., is thought to involve a reduced amount of autophagy in nervous system tissue where it’s supposed to always be going on, at least at a low level. I think part of it is genetic - the tendency to develop cognitive problems, and likely the extent to which the body can stave them off.
While here too I haven’t seen proof of how it usually progresses, it makes sense to me that the body would take the “low-hanging fruit” first. As a cell gets the old/faulty stuff removed, it also makes sense that the number of autophagosomes required in that cell would decline.
As a fast goes longer and longer, the body is still excreting some nitrogen, and there’s a net protein loss - from memory it’s around 15 or 20 grams per day. I wish I knew how the scavenging proceeded - and there are probably differences between individuals, just as some people readily consume loose skin while others retain almost all of it.
GKI and autophagy - what bugs me about this is that GKI is so heavily dependent on diet composition and metabolic health. One person, eating ketogenically, can have quite low blood sugar and quite high ketones, while another, insulin-resistant and not fat-adapted, can have blood sugar remaining higher and ketones relatively low, even though they haven’t eaten for a while. At the least I’d think we need to consider one’s individual situation.
Good discussion. Agreed that when things get static, then ‘the clock is running’ as far as some good things likely happening at the maximum rate. My problem is that equating the GKI with autophagy just doesn’t make sense, so often. Glucose and ketones do go toward or come from insulin levels, glucagon secretion, etc., so I do think they’re connected, but I’d rather see the mTOR/AMPK Index than GKI.
Additionally, if we’re looking for “what is best for me to do,” then I think of things like the total amount of fasting, and my gut feeling is that it’s better to fast for 5 days, four times a year, versus doing one 20 day fast. There are also very good things that happen for us during the refeeding period after a fast, and while I have no idea how to quantify it, I’d think that more cycles of refeeding in a year (for example) would be better than fewer, to a point.
Definitely, Bob. mTOR/AMPK is the single largest thing (as far as I know) in determining the rate of autophagy. And of course it’s more complicated than just one overall rate… Even while eating normally, whatever that is for an individual, exercise can induce autophagy in skeletal muscles. And, tissues made of cells that can’t divide and renew themselves - like much of our nervous system - need more “house cleaning” to keep things working right, and they usually are supposed to have some autophagy going on all the time, regardless of eating or not.
In looking at it again, I am reminded hat the GKI probably can go lower than 0.5 for quite long extended fasts, although probably not under 2.5/8= 0.3125, and the first “leveling” appears as noted above (I would consider this to be the baseline “reset” levels).
No problems, Michael. The learning is the important thing.
Thanks for that link to Valter Longo paper. Looks like a good read while the morning coffee soaks in.
I had seen Dr. Boz’s use of the GKI to determine autophagy and I’ve been skeptical of it. It’s hard to explain why I got that feeling, but it seems more like a correlation rather than a direct cause and effect relationship to autophagy. Admittedly, it’s hard to examine yourself at the cellular level to look for autophagosomes to prove it’s happening, but that would probably be the absolutely best way to know. The number and activity of your autophagosomes has gone up, so you know it’s happening.
I’m going to try to put together analogy. Since I live in a hurricane-prone area and we’re at the peak of the season, this comes to mind. Say I want to determine if a hurricane is happening. I look outside and see lots of rain going sideways horizontally, then I see pieces of trees and somebody’s rain gutter blowing by. That’s an effect of a hurricane but it could be caused by another kind of storm - a tornado or particularly strong thunderstorm - so stuff blowing around is correlation, not proof. I look at the beach and see reporters all doing dramatic shots of the wind blowing them around. That’s a correlation with the storm; the storm didn’t cause the reporters to put themselves there; their bosses (or their own urges) did. It tends to happen repeatably when a hurricane is happening, but it’s not an effect of storm and certainly not a cause, but it correlates reliably with a hurricane.
What if, somehow, those levels of GKI are an effect of autophagy going on but not the cause? When autophagy turns on that changes the glucose and ketone numbers causing GKI to change.
The missing piece of information is how well GKI correlates to the level of autophagosome activity, and I doubt that work has been done.
So there you go. Enough coffee to think of a silly correlation vs. causation story, but not enough coffee to keep me from posting it.
Absolutely true. My blood and breath ketones over time. Could have low GKI at one time. Now, I only get low GKI if I fast multiple days, and even then only in the evening. Blood glucose is too high in the mornings, ketones too low, even when fasting 4.5 days.