Calorie restriction (CR) is the most robust and effective life-extension intervention known, and intermittent fasting shows great promise in life extension as well. (I’ve written extensively about both calorie restriction and intermittent fasting on this site.) The question, unanswered so far, is how they work, although many possible explanations have been offered. Many pieces of evidence point towards the production of ketones as being the underlying, unifying factor, in which case calorie restriction, fasting, and the ketogenic diet have the same anti-aging effect.
Ketones mimic effects of calorie restriction
Ketogenic diets extend lifespan in lab animals. Does this diet extend lifespan through the same mechanisms as CR and fasting?
Consider that a reliable outcome of CR is the production of ketones. Intermittent fasting also results in ketone production, in fact, larger than calorie restriction. Obviously, ketogenic diets produce ketones also.
Ketone bodies mimic the effects of calorie restriction. Ketone supplements do much, if not exactly, the same thing as a ketogenic diet. Ketones lower insulin signaling and blood glucose, key elements that have been shown to affect lifespan in all kinds of lab animals from yeast to C. elegans (a worm) to rats.
One of the biochemical pathways thought to be crucial in aging is mTOR (mechanistic target of rapamycin). The ketogenic diet inhibits mTOR. Whether it inhibits it to the same degree of CR or fasting isn’t known; likely much more research would be required to find out.
The ketogenic diet stimulates mitochondrial biogenesis, as does CR and fasting. It lowers oxidative stress by upregulating antioxidant defense mechanisms. The ketogenic diet stimulates autophagy.
The ketogenic diet is well known to result in loss of excess body fat, as are CR and fasting, and reduction of excess body fat is thought to be a major mechanism of CR in lifespan prolongation. This aspect gives me a little pause in the comparison, because it’s possible that, while ketogenic diets help fat loss, they don’t universally decrease it to low levels. It’s perfectly possible, although perhaps difficult, to gain fat mass on a ketogenic diet.
What accounts for effects of CR
Are the effects of CR due to reduced calories in general, or reduced protein, carbohydrates, and fat? Or maybe CR is just a form of fasting, since animals on CR eat all their food at once.
Between 70% and 100% of the effects of fasting are due to carbohydrate restriction.
The lower figure, 70%, comes from a study in diabetics in which they either fasted or ate a VLCKD (ketogenic diet) for 3 days. One could argue that had the experiment used a longer time period, the values for fasting and ketogenic diet may have converged, since benefits of zero carbohydrate intake usually take longer than a few days to manifest completely. (Although the study did show that you get instant benefits by restricting carbohydrate.)
The higher figure, 100%, comes from a study in which volunteers either fasted or fasted with a lipid infusion that gave them all their caloric requirements. There was no difference between the groups in plasma glucose, free fatty acids, ketone bodies, insulin, and epinephrine concentrations, which led the researchers to conclude: “These results demonstrate that restriction of dietary carbohydrate, not the general absence of energy intake itself, is responsible for initiating the metabolic response to short-term fasting.” However, the researchers seem to have missed the fact that neither group of volunteers consumed any protein either, so their conclusion seems premature.
Many scientists in this field place great emphasis on protein restriction as important, for instance Valter Longo and his fasting-mimicking diet. However, recent experiments have found no effect of protein restriction on the metabolic and biochemical parameters affected by CR. Some data shows otherwise, but this major series of experiments by John Speakman and colleagues, and their null results with regard to protein restriction, cast serious doubt on the idea that it will prolong lifespan. For what it’s worth, in my opinion protein could be important, but distinctly second in importance to restricting carbohydrates.
Fasting and CR have a great deal in common with the ketogenic diet, with many overlapping if not identical effects, including the extension of lifespan.
Is it even necessary to restrict calories or fast, or does one need merely to follow a ketogenic diet? While CR and fasting may offer benefits beyond the ketogenic diet, it seems probable that the ketogenic diet gets you at least ~90% of the benefits of CR and fasting.
While fasting may not be super difficult, it’s not exactly pleasant, either. I would imagine there’s a marked stress response in us that we may not know the full extent of. Hopefully, your question about its necessity will get definitively answered one day. It would be nice to think we could have all of the benefits mentioned with a ketogenic diet alone.
Right, TeeDee. On the other hand, the keto diet is a hard sell for many people too.
IF is like a metabolic workout. As you get more used to it, the easier it becomes. Or did for me anyway, when I started doing it a year at.
For the past several months my colleagues and I have done an experiment on ourselves and compared notes. Eli did CR with intermittent fasting , Daniel fasted 3 consecutive days a week, and I started weekly rapamycin. From a purely symptomatic point of view l’m the winner.
Thanks for that, Paul. So that could mean rapamycin outdoes those strategies.
Perhaps so . Rapamycin is probably a superior mTOR inhibitor, but of course I’m running more of a risk.
Well, Dr. Rivas, if I may…what sort of risk(s) are you referring toward?
On 2mg once a week my risks are actually quite minimal since I keep dosing it a trough level that is close to zero.This transient inhibition of TOR1 isn’t enough to inhibit TOR2, so immunosuppression isn’t an issue. It does give what Blagosklonny describes as an innocent ” starvation” hyperglycemia, while lowering IGF and fasting insulin levels ( my fbs is 115 now). I also lost an amazing 15 lbs in 2 months effortlessly ( alot for me) and that was accompanied by an increase in lipid levels, which I don’t really worry about. I only care about my coronary calcium score staying at zero.
I have to say that I do feel about 20 years younger on it, but that took close to 3 months to occur.
I’ve been following a restricted calorie (zero carb) ketogenic diet. I find calorie restriction easier to follow than intermittent fasting, because my portion sizes are smaller and that seems to be easier on my digestion. I really feel good and don’t get hungry!
Interesting, Mellie. Anecdotally, women seem more likely to go that route. I tend toward fasting and big meals.
Very interesting article Dennis – particularly about the relative ineffectiveness of reducing protein. Longo would surely have something to say about that study – but I am happy as I have recently upped the protein in my diet to 2g/Kg/ day: aiming to get 50g protein at each of 3 meals per day. Except when I IF for 16-18 hours 3 days per week (to lower MTOR and activate AMP-K) by cutting out breakfast and having a late lunch. I do eat a bit more protein though on the remaining 2 meals to get close to the 150g/ day target – not easy in 2 meals though!. Never felt so good, so would be surprised if high protein was detrimental.
One thing that did stand out to me in the Speakman study that showed no effect of protein restriction (PR) was the relative value of methionine restriction (MR), which they claim operates on a different pathway to CR. Although MR is very difficult to achieve in practice, other studies have shown that the exact same effect can be achieved by upping your glycine instead. So that’s what I do: supplementing with 8g of glycine powder or hydrolyzed collagen powder each day. Here’s the extract I am referring to: “Interestingly, unlike PR, changes in body composition, particularly reduced visceral fat, accompanied MR with subsequent reduction in insulin, glucose and leptin . Although some believe MR to play a contributory role in CR effects, comparisons of gene expression profiles do not significantly overlap, suggesting independent pathways between CR and MR .”
Those are very good points. I’ll up my glycine. I suppose that you are aware that mitochondria get glycine depleted as we age.
If you haven’t done so already you should read the work of Blagosklonny on TOR and weekly rapamycin, especially his 2017 article in Oncotarget on anti-agimg and rapamycin analogs. I was very hesitant to try it but the results have been dramatic ( at least for me at 62).
As for fasting my partners and I have accrued multiple studies on it and essentially,
Autophagy peaks and plateaus out at 24-36 hrs.
Mitophagy at 24 hrs
PC-SK 9 inhibition at 48 hrs
I’m fine with 24 hrs once a week but my partners do more. All are doing well.
As far as visceral fat is concerned, there is evidence that macrophages inhibit the activity of catecholamines in visceral fat and this can theoretically be corrected with the supplement feverfew.
Hi Paul, very interesting points you make there. Yes, there are lots of papers I have seen now on the benefits of glycine so considering it is so cheap I would definitely go for that. It’s a vital component of both glutathione and endogenously produced creatine amongst others. There are some schools of thought that it could be even more potent in the form of hydrolysed collagen powder (maybe because it also contains proline which may be synergistic with glycine – but the evidence seems lacking on that one).
I do bodyweight HIT resistance training workouts on Mondays, Wednesdays and Fridays and have achieved some decent improvements to body composition as a result of that coupled with the 16-18 hour IF on my ‘off’ days, and also I believe my high protein diet plays its part too. I had been reticent to push past 18 hours IF as I didn’t want to to push my body too far into catabolism – but maybe I will re-think that if autophagy peaks at 24 hours. After all, in terms of protein synthesis it seems the ‘refractory period’ is just as important before hitting it with a high-leucine bolus of protein (I usually go with 50g of whey protein isolate) to break the fast and activate MTOR. Even Longo seems to agree that the protein re-feed is where the magic happens (although he would of course advocate a much longer fast beforehand)!
I have listened to a few podcasts touching on rapamycin and although it holds a lot of promise I have been a bit wary of the risks to be honest. Also at 46 years old, I’m guessing I may be able to leave that one for a little later.. I do however take berberine, aspirin and resveratrol on the evening of my IFs, so hopefully hitting some of the same pathways. But I will keep a watchful eye on the rapamycin research as it develops. As an aside, I think I remember on the Tim Ferriss podcast David Sabatini (the discoverer of Rapamycin) saying that he didn’t take it himself which raised the warning signals in my mind.. Still, definitely one to keep an eye on!
good points. Be somewhat careful with berberine since a mouse study showed that it was safe at 5mg/kg/day but gave significant immunosupression at 10mg/kg.
As for rapamycin,it’s certainly not safe taken daily, but very much so on a once a week basis. No one knows more about it than Blagosklonny, and he takes it. But you are still pretty young.
Hi Paul – thanks for the heads up on the Berberine – I appreciate it! I weigh 71Kg currently, and my Swanson berberine capsules are 400mg – so that works out as 5.6mg/kg/ day. I was taking it the first evening of my 16-18 hour fast and also the following morning, but think I will drop down to evening only, based on your advice. Since going paleo a while back I had drastically reduced the number of colds/ minor ailments suffered but recently had noticed I was coming down with every cold going round – maybe the berberine played in part in this since the timing seemed to coincide… I wonder if anyone is aware of similar upper limits exist for other AMP-K initiators such as resveratrol, aspirin, glucosamine, grapeseed extract – all of which I take on the evening or following morning of my fast, 3 times per week?
It was an alkaloid effect rather than an AMPK effect since none of those substances, or even metformin are linked in any way with immunesuppression at any dose.
I also cut my dose back of berberine and would re-start metformin if it didn’t fatigue me so much.
I also take all that you take ( and many more).
Thanks, Rob. Methionine restriction seems to be a kind of special case. It’s odd that protein restriction has little to no effect, since when you restrict protein you restrict methionine. I eat plenty of protein myself, and given the relation between protein consumption and less visceral fat, that might even extend lifespan.
Personally, I believe there’s a widespread bias among researchers, based on “natural” and “green’, e.g. fruits and veg and vegetarianism and low cholesterol good, saturated fat, meat, high cholesterol bad. Lots of this has to do with recent dietary fads of low cholesterol and low fat etc., but a lot of it goes all the way back to the Garden of Eden or Pythagoras, the idyllic times when we didn’t have to kill animals to live and our food fell off the trees and we had no disease.
Perhaps you could reconcile a couple of concepts that are related but in my mind, still very opposed in their sum total effects upon human physiology. Most people who read your blog and others of its ilk are quite familiar with the concept of IF, CR and ketogenic eating. The initiation of autophagy is a huge benefit of these metabolic up-regulations. This is not controversial information. However, the lesser understood concept of ferroptosis is where things get a little murky. Autophagy is, by all means, a positive state of physiology. Ferroptosis is the breakdown of ferritin and unless I’m incorrect, essentially the result of ferritin autophagy. Thus, this particular version of autophagy results in highly volatile free iron being released upon the physiology…which is not exactly a great situation to have happen…providing of course, if you’d rather save your glutathione for other oxidative events and keep cellular damage to a minimum….
Aside from perhaps a very reductive synopsis of biological processes, what am I missing here?
I don’t know that you’re missing anything. The idea behind minimizing ferroptosis is to keep ferritin low normal and glutathione high. I think it’s well agreed among scientists that enhancing autophagy is a good thing, or at least restoring it to youthful levels. But it isn’t 100% beneficial; cancer cells may use autophagy for example.
Interesting point about the utilization of autophagy by (some) cancer cells..
However, if ferritin is essentially the material that stores free iron (to constrain iron’s volatility), it stands to reason that ferritin counts would be lowered only if total iron were lowered….if total iron load remained unchanged, there would be no need to minimize ferritin as less ferritin, in that case, would certainly mean more free iron “run amok” in the physiology. This is precisely the paradox that I am struggling with.
Many readers are of the mind that IP6 is only useful as a chelator of free iron and not iron that is already “spoken for” by ferritin. Personally speaking, I can tell you that this is not merely the case for me and that I have seen IP6 work relative wonders for lowering my total ferritin counts from last October on a quarterly basis. Of course, perhaps this is due to a signalling event that IP6 initiates so that ferroptosis can proceed; at which point the IP6 is situated to “grab” the newly freed iron.
In this regard, could it be that IP6 or other chelators might be seen as the driver of therapuetic ferroptosis. Otherwise, without the presence of chelators, ferroptsis would mean the release of free iron and that is a very biologically taxing event; something that seems to be at odds with the chief aim of autophagy.
Well, ferritin is the chief form of storage iron. Other forms of iron (hemoglobin for instance) have strict limits to their production, but ferritin can rise without limit. Ferritin’s only function is iron storage, so if iron is lowered say via blood donation, ferritin goes lower, and the body will preserve iron for necessary physiological functions, such as hemoglobin. That’s why you don’t see anemia (low hemoglobin) unless ferritin has already bottomed out and is at very low, usually single digit levels.
As for IP6, seems doubtful that it gets iron from ferritin, though it could get iron from transferrin, the iron transport molecule. My idea is that as IP6 grabs free iron, of which there’s always a small amount circulating, it drives the equation so that ferritin drops. But I don’t know how that might fit in with ferroptosis.
In summary, lower total iron means lower ferritin, and beyond ultra-low ferritin you get into disease states like anemia.
What I’ve done is go very low, almost no, carb. I started in May and since that time I’ve lost fat but no weight (I lift full body 3 times a week). I eat meat, veggies, fruit, cheese, nuts, and supplement with whey isolate.
It took a long time, but I lost my spare tire and man boobs. Now if I could quit drinking alcohol I’d be solid!
Anyway, I went this route cause fasting was to brutal on me. Fuzzy brained, didn’t feel food. But now I eat a lot if I want to, and with the resistance training I’ve slowly burned off the fat. I don’t look as big, but a significant amount of that bigness was dough. I like being big, but not soft – and definitely not fat in unattractive places.
Keep up the good work, Dean!
A few comments on the comments here:
– Many people just assume that fasting is a more extreme form of CR however the scientific and anecdotal evidence seems to say that there are two important differences. First, fasting, assuming it is offset by periodic feasting, maintains a health metabolic rate, whereas calorie reduction generally does not. This accounts for why typical diets often don’t work, since the body downregulates “calories out” and low metabolism symptoms arise. This was recently shown in the Biggest Loser study, among others.
– Fasting, once someone is adapted to it, seems to be much easier to follow, and is often enjoyable, in comparison to frequent low calorie eating. I have experienced this myself when I was perfectly happy not eating, but even a little bit of food suddenly triggered a strong urge to eat more.
– Longo’s “Fast mimicking diet” and the recent study that claimed to evaluate fasting but which actually used low calorie feeding, both seem to suffer from not adhering to the principles above.
– Regarding the possible risks of mTor inhibition, the big one from my perspective is the potential for reducing the exercise benefits, especially strength training, potentially making one more injury prone, and/or making recovery from injuries more difficult. Hopefully this is not an issue as I am ramping up my Metformin use (in an intermittent manner) and it is also an mTor inhibitor, although much of that affect may come from its insulin-lowering affect which low-carbers should have already achieved. I don’t have any evidence that the above risk is an issue, however mTor is there for a reason and it seems logical that even periodic inhibition might impair injury recovery, especially joint injuries.
– I would strongly encourage anyone interested in these topics to follow the blog writings, podcasts (Fasting Talk) and patient reports from Dr. Jason Fung as he seems to consistently have the most experience and insight into these topics. I believe has put more than a thousand patient on medically supervised fasts and his writings are where I learned the points above.
– I believe also keto and lower carb diets also promote a high metabolic rate which is another reason why they generally work much better that calorie lowering alone.
I very much agree with all of your comments. TOR is of course there for a reason. It is the cellular sensing agent for nutrients and energy requirements and is the primary cellular driver for growth and development. That is a great thing up to the age of 25 or so but then it doesn’t know to slow down. This results in the geroconversion later in age from arrested cells to the ever growing but dysfunctional and mostly harmful senescent cells. The resultant damaging hyperffunction fromTOR without brakes leads to most, if not all age-related diseases.
Rapamycin does not fully inhibit TOR but suppresses it, and this is particularly true at weekly pulsed dosing regimens.
CR, IF, and metformin all do effectTOR to a lesser degree, but having tried them all, nothing compares to rapamycin. Injury repair doesn’t seem to be an issue even in some elderly people now on it for 2 years.
Thanks for sharing your comments and experience. This is something I’m watching closely to potentially try, however right now, thankfully, there’s not much I can point to as obvious signs of aging although there may be things I can’t detect. Chronic injuries and occasional joint pain are the two primary candidates so that is why I am so focused on that topic. I tend to be a late adopter but at some point I think I will add in the rapamycin as there seems to be little downside.
I avoid medications like the plague so I fully understand your reticence Drifter.
Hi Dennis, this is a bit off-topic I know (apologies) but have you written anything about the potential benefits of intermittent sleep restriction ( eg once per week) for those of us that sometimes suffer from difficulty sleeping/ low mood? Maybe facilitated by a highly targeted, significantly increased caffeine intake once per week coupled with a highly ketogenic diet? If not, would you be amenable to a reader request to examine this issue – I think it’s right up your street?!
Hi Rob, I did write about the issue of sleep deprivation as depression treatment, but it’s been awhile. I see no reason why someone couldn’t just do it, but there are a few caveats. 1) Sleep deprivation therapy works for major depression, but that doesn’t mean it would work for garden variety blue mood, although my experience is that it does elevate mood, even if you’re not depressed. (My experience working 2 graveyard shifts every 2 weeks.) 2) People with tendency to mania shouldn’t do it, and in fact anyone with a serious health problem should talk to a doctor first. 3) Complete sleep deprivation for one night isn’t necessary, as 4 hours deprivation is found to be nearly as effective.
Many thanks Dennis, I thought I remembered something you had written on this subject. I was just wondering because I found myself drinking way more coffee than usual yesterday and lying awake in bed for several hours. Rather than getting anxious or taking my usual passiflora tablets (which work a treat I have to say, but can leave one a little drowsy the following morning) I just relaxed this time and went with it, curious to see if sleep would come of it’s own accord. It didn’t – but I am functioning today just the same as ever, so it made me wonder whether this might not be such a bad thing to do once a week to ‘reset’ sleep patterns similar to a 24 hour fast for diet… I might try it once per week to see whether my overall sleep on the other 6 nights improves as a result…