Anti-Aging Studies Are Seriously Compromised


Valter Longo, the noted scientist in aging research, has published a number of studies about fasting as an anti-aging measure. He’s developed a fasting-mimicking diet to be used for extended fasts, which I wrote about here. He and colleagues have a new study out, but the question in my mind now is, does the fasting-mimicking diet work? It may not be as effective as advertised, because anti-aging studies are seriously compromised, including this one.

Extended fasting

Intermittent fasting is the practice of going without food for some period of time. An intermittent fast would usually last a minimum of 16 hours, and extend to 24 hours, perhaps more. Definitions in these matters are not totally arbitrary, but are rather loose. Beyond 24 hours or so, a fast that extends into days, would not be an intermittent fast, but an extended fast.

Previous studies have found anti-aging effects, including immune system regeneration, with extended fasting. Keep in mind that when a mouse or rat is fasted for several days, that’s a very long time in human terms.

The current study looked at humans on a fasting-mimicking diet.

Fasting-mimicking diet

Extended fasts of several days can be difficult, if not physically then psychologically, and to get around the difficulty, Longo has developed a fasting-mimicking diet. (Discussed in my previous article.) The idea is that a low-calorie, low-fat, low-protein diet for 5 days will not raise insulin of IGF-1, and thus this diet effectively, or nearly enough, physiologically mimics complete fasting.

The current, just-published study is called “Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease“. A layman’s summary says:

Fasting: More than a fad

Mice that fast periodically are healthier, metabolically speaking. To explore whether fasting can help people as well, Wei et al. studied 71 people who either consumed a fasting-mimicking diet for 5 days each month for 3 months or maintained their normal diet for 3 months and then switched to the fasting schedule. The fasting-like diet reduced body weight and body fat, lowered blood pressure, and decreased the hormone IGF-1, which has been implicated in aging and disease. A post hoc analysis replicated these results and also showed that fasting decreased BMI, glucose, triglycerides, cholesterol, and C-reactive protein (a marker for inflammation). These effects were generally larger in the subjects who were at greater risk of disease at the start of the study. A larger study is needed to replicate these results, but they raise the possibility that fasting may be a practical road to a healthy metabolic system.

In sum, the participants decreased:

  • blood pressure
  • body weight and fat
  • IGF-1, the growth hormone implicated in aging
  • blood glucose
  • cholesterol
  • triglycerides
  • C-reactive protein

However, a significant caveat to the above is that changes in glucose, triglycerides, and C-reactive protein overall were not significant; an analysis revealed that changes occurred only in high-risk participants.

One would have to agree that these results look great, and if so, why do I question whether the diet worked?

The answer lies in the baseline values of the participants.

  • Only ~37% were of normal weight, with ~39% being overweight (BMI between 25 and 30), and ~24% being obese (BMI >30). The subjects were on average somewhat leaner than an average group of Americans, but not much.
  • Body fat: the paper gives body fat in terms of total volume, but lean body mass in terms of percent; doing a calculation reveals that the average body fat percent was about 34%. Even with the fact that over 60% of the participants were women, that’s a lot. They were fat.
  • What did they eat normally? No information is given, but the average American eats 20 teaspoons of sugar daily, and the diet of the average American is 50% carbohydrate.

My point is that the participants who ate the fasting-mimicking diet were fairly typical: they were overweight, had high body fat and low muscle mass, and most likely ate like the typical American with plenty of processed junk.

Of course if you drop their calorie intake and they eat less crap food, they’re going to have better health markers. That’s a given.

What about people who already eat well, with a carbohydrate percentage well under 50%, with no refined carbs or sugar or vegetable oil, no processed junk food, and who have low body fat and exercise regularly? Is the fasting-mimicking diet going to strongly decelerate your aging?

Not likely.

Calorie restriction may not even work

A similar phenomenon is at work in animal studies of calorie restriction, which is the most robust life-extension intervention known.

The food that scientists feed lab rats and mice is garbage, loaded with sugar and vegetable oil and toxic amounts of iron. Do you think eating less of that will extend their lives? Not surprisingly, the answer is yes.

Lab mice and rats that are used as controls in calorie restriction studies are metabolically morbid. With their garbage food, and kept in cages with little exercise, the average control rat or mouse becomes obese as they age.

So the question arises: does calorie restriction really extend lifespan by slowing aging, or do the animals just live longer because they don’t become obese or develop diabetes?

Calorie restriction does not appear to extend the lifespans of wild mice.

Below is a chart of the weight of (lab) rats throughout their lifespans. (From here.) Rats are fully mature, according to the same article, at 5 to 6 months. Do wild rats gain weight after maturity? That seems doubtful to me, and very old rats, assuming they survived long enough in the wild, would be likely to lose weight. But in the laboratory, they gain weight steadily throughout life, and that does not seem normal. They become metabolically morbid and overweight/obese.

Any intervention that prevents their weight gain will prolong their lives, but that does not mean it will prolong the lives of normal rats or humans.

Added: In “Impact of caloric restriction on health and survival in rhesus monkeys: the NIA study“, the authors discuss why the NIA monkeys did not show an increase in lifespan, while in another study, the WNPRC, they did. Answer: the control animals in WNPRC were fed junk diets with nearly 30% sucrose – yes, you read that right, the control animals got tons of table sugar.

A notable difference between the two studies is the composition of the monkey diets…. 

Fat content of the NIA study diet was derived from soy oil and the oils from the other natural ingredients (i.e. corn, wheat, and fish). Fish meal contains approximately 8–12% fat and is rich in omega-3 fatty acids. The WNPRC study dietary fat was derived from corn oil. [Corn oil is known to promote cancer.] Carbohydrate content was also strikingly different; although both diets have 57–61% carbohydrate by weight, the NIA study diet was comprised primarily of ground wheat and corn, while the WNPRC study diet contained corn starch and sucrose. Indeed, the WNPRC diet was 28.5% sucrose, while the NIA study diet was only 3.9% sucrose. This latter point may be particularly important as a diet high in sucrose can contribute to the incidence of type II diabetes.

Drosophila melanogaster, the fruit fly, is often used in studies of aging. Over a 3-year period of adaptation to laboratory conditions, they undergo a rapid loss of stress resistance. One might look at these as the fly equivalent of obese lab animals or humans. Studying aging in this population will give faulty data.

In my opinion, this is a scandal.

Conclusion: Aging studies need an overhaul

Fasting studies in humans and calorie restriction studies in animals both appear to suffer from control groups that are metabolically morbid. Sick people and animals.

The majority of Americans, about 80%, are not 100% healthy and suffer from chronic health problems to one degree or another. If a diet, a fast, or other regimen corrects some of those problems, that does not mean that it slows aging, only that the participants became less metabolically morbid.

If a calorie restriction regimen extended animals’ lives, much of the time that might be only because they were prevented from becoming obese. Wild mice may be living optimally for life extension already, and restricting their food in wild conditions may do nothing. What they need is protection from predators.

What’s needed are studies using metabolically healthy humans and animals at baseline, and then finding out whether a given intervention helps them. But good luck with that. Cost and convenience are huge factors in any scientific study. Labs don’t want to pay staff to come in to feed animals on weekends, for instance, and they want to use the cheapest, most convenient food.

Lab food contains toxic levels of iron, up to 10 times the requirement, and as animals age, their body iron stores increase dramatically, causing misfolding of proteins and oxidative stress and sarcopenia. Hey, maybe it’s the food? I’ve hammered on this topic, but expect it to go nowhere as usual.

I’ve lately become much more skeptical about studies in aging, and those are the reasons why.

PS: Here’s the talking head version in which I discuss the various fasting and CR experiments and what they mean for the science of aging.

PS: Check out my books, Dumping Iron, Muscle Up, and Stop the Clock.

PPS: You can support this site by purchasing through my Supplements Buying Guide for Men.

PPS: I was contacted by the new site and asked for a mention. Looks to be a very worthwhile site dedicated to the science of aging, and written by professionals.

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  1. neven says:

    I think something similar happened with 2 long haul monkey CR studies. In one (the first major one that everybody is quoting), they were fed garbage, and CR showed a significant benefit, whereas in the second study they were fed a healthy diet, and the difference between CR and non-CR groups was negligible.

    • P. D. Mangan says:

      Yes, I’ve read that too. Apparently their diets were loaded with sugar.

      Added: I found this:

      Additional differences between the two diets include the source of nutrients. Protein sources for the NIA study include wheat, corn, soybean, fish, and alfalfa meal, whereas the WNPRC diet protein source was lactalbumin. The NIA study diet also contains flavonoids, known for their antioxidant activity and specifically, isoflavones with estrogenic activity, which may contribute to decreased arterial stiffness21, 22. Fat content of the NIA study diet was derived from soy oil and the oils from the other natural ingredients (i.e. corn, wheat, and fish). Fish meal contains approximately 8–12% fat and is rich in omega-3 fatty acids. The WNPRC study dietary fat was derived from corn oil. Carbohydrate content was also strikingly different; although both diets have 57–61% carbohydrate by weight, the NIA study diet was comprised primarily of ground wheat and corn, while the WNPRC study diet contained corn starch and sucrose. Indeed, the WNPRC diet was 28.5% sucrose, while the NIA study diet was only 3.9% sucrose. This latter point may be particularly important as a diet high in sucrose can contribute to the incidence of type II diabetes23, 24.

      The CR monkeys in the WNPRC diet lived longer, because they weren’t eating sugar.

  2. James says:

    Yes, some of extended fasting studies don’t use the best baselines…


    The biological and evolutionary logic that makes intermittent fasting so powerful is exactly the same that makes extended fasting so powerful.

    Accordingly, we have good reasons to think, to bet, that the aforementioned results will easily be replicated in healthier individuals.

    Yes, if you’re 4% body fat, an 80 day fast might well be more costly than beneficial.

    But if you’re 12% body fat, a 14 day fast is likely deliver advantages that significantly outweigh costs – advantages that can only be generated by fasting beyond 16 to 24 hours a day.

    It would be wonderful if doing 16:8 intermittent fasting were sufficient for optimal autophagy. But I seriously doubt it: deeper damage needs deeper cleaning.

  3. Dennis –
    Thought-provoking points you make, as always. Yes we need better controls in CR experiments of all sorts. It’s an embarrassment that many of us don’t want to think about that there are some strains of mice in which CR actually shortens life span. In any case, the whole CR pathway is likely to control ~7 years of human life span, nothing like the 40% available in mice or the 100+% available in worms.
    It’s certainly true that CR and fasting will offer more benefit for the obese than for the already skinny. But I don’t think it’s tenable that the only reason CR works is that “if you’re eating crummy food, the less of it the better.” The data is too robust over many species and situations, and I believe in the theory that says the CR response was invented by evolution to help level the death rate in times of plenty and in famines.

    • P. D. Mangan says:

      Josh – thanks. Doesn’t the length of time that CR might control in humans depend on which theory of aging one uses? For instance, Kirkwood said that CR was unlikely to extend human life much because humans devote so much less of their life strategy to reproduction than do mice. De Grey thinks that CR is only a strategy to survive a bad season, so absolute life extensions would be similar in humans and mice, e.g. 1 year for each. If those theories are not correct, results may be different. As animals get bigger, they seem to get more out of CR in relative terms, e.g. a few weeks (I think) for Drosophila, a year for mice, more for rats (?), so as far as I can see, that point isn’t settled. I do agree that for, say, C. elegans, lab food doesn’t seem to be an issue, although if you give them sugar and iron their lives are shorter. But even there, or with fruit flies, they’re all getting some kind of lab food, yeast and sugar in the case of flies.

      • Josh Mitteldorf says:

        You’re right — I should back off the theoretical arguments. I don’t think evolutionary theory has any predictive value in the area of nutrition. For humans, there is good evidence that people who eat less are healthier in lots of ways. Whether that translates to a longevity increment remains to be seen.

  4. Montgomery says:

    So what most studies of the past in CR actually showed looks much like mere normalization, forcing animals and humans back into simply being lean by preventing overeating with garbage-tier food: Just taking away an artificial stressor in form of wrong quantity and quality of food.

    Good thing that we have objective measurements like these:
    -blood pressure
    -blood glucose
    -C-reactive protein
    All of these represent being healthy if they are in the lower range and mean trouble if they are elevated.
    Higher values are strongly correlated with additional body fat, the more fat the higher values; of course there
    are other causes/diseases to elevate these values in some slim people, and those would then limit life-span, too.

    So, we are back at old “The fatter you are, the sicker you are , too, and the less long you will live.”
    No surprises here, a quick glance at people 90+ or even 100+ sure shows no fat people; as far as I can
    tell, they are mostly thin as sticks; there are practically no really fat old people.

    • Josh Mitteldorf says:

      The idea that “evolution has prepared us to eat less, so eating more is bad for us” doesn’t get you very far. In fact, there is evidence that evolution has given her children two modes of being: (1) Hunker down and live out the famine, and (2) reproduce fast and furious, then get out of here. You can see clear evidence of this in mammals, but it is super-obvious in lab worms, where the body actually takes two different forms in these two modes, the metabolism is completely different, and lifespan can be extended more than tenfold by complete starvation (zero food).

  5. bigmyc says:

    Slightly on topic question; You had mentioned that the interval reading of fasting insulin is between 2.6 and 24.something.. I believe yours was around 2.9. Obviously, if your reading is at the higher end, it’s something to be concerned with but what if one’s fasting insulin is lower than 2.6? I just received my results and it is 1.6. I’d be proud if I wasn’t slightly worried. LabCorp has it “Flagged” as “low.”

    • P. D. Mangan says:

      Seems that several things can cause low fasting insulin, but normal ranges are constructed from the values of 95% of normal people, so it’s possible that a number like that is a mere outlier.

  6. BC says:

    Two points for consideration.

    First, the “Twinkie Diet” results:

    Second, while insulin sensitivity is affected by various factors, doesn’t (promotion of) autophagy still require some type of fasting?

    I remain, tentatively, a believer.

    • P. D. Mangan says:

      BC: I remain a believer too. See my comment downstream. Re Twinkie diet, the man in question counted calories, and there’s no denying that that can work so long as you are disciplined and don’t let your hunger get the better of you. I admit a 27 pound loss in 2 months is impressive.

      Promotion of autophagy does generally require fasting and /or a calorie deficit.

  7. Montgomery says:

    Would it be worth taking a look at people who already are very muscular, have exceptionally low-body fat and live also very calorie-restricted?

    Worldwide there should be at least some 1000s of these people, men and women – I speak about those extremely determined bodybuilders with body-fat so low they look veiny – you know the type, often very tanned, some say they look like “human chicken”.

    This group has to live under what seems to me very CR-conditions over long periods of time to stay that extremely lean.
    It may be interesting to take a look how their health and aging markers compare to non-overweight, regular people.

    • P. D. Mangan says:

      One thing about even very determined bodybuilders as in the photo is that they eat plenty but burn it off through exercise. A study looked at whether exercise could do the same things as CR and found that it didn’t. So while these people may be quite healthy – or possibly not – I don’t think that they necessarily get a great anti-aging benefit from it.

  8. Montgomery says:

    I thought about the observation that some overweight people under conditions of LCHF lose body fat even when not eating hypocaloric.
    This has always fascinated me, because I was under the impression that we are evolved to maximize
    our energy intake from food, which seems to me useful/optimal for survival in a famine-prone environment.

    I wonder if the reason that carbs, especially simple ones, are so fattening, is simply that we have no evolved
    pathways to reject sugars?
    Years ago I read about feces – it turns out that, depending on diet and other factors, there are a lot of useful
    nutrients left un-absorbed found in feces – fats, but also some minerals and vitamins; in feces of people
    who are starved or lacking certain nutrients, these are then practically completely absorbed, however.

    There are differences in gut absorption of nutrients depending of the current need of the body, for example
    some minerals can be absorbed most efficiently or practically blocked from absorption.

    What if that auto-regulation would also happen with fats? Then the body could potentially stop absorbing fats at some point, preventing itself from getting overweight the same way some minerals are blocked
    from absorption when they are abundantly available. It would explain why aome overweight people on LCHF lose weight even when they eat somewhat hypercaloric.

    Maybe the fattening and illness-inducing effect of a high sugar diet is all about the fact that sugars cannot be non-absorbed or eliminated from metabolic pathways and have to be processed and stored, no matter what?
    (Certain minerals and vitamins are removed when absorbed and available in oversupply and quickly
    leave the body by urination.)
    Could we be evolutionary well-equipped to deal with overfeeding from protein and fats, but
    in our evolutionary metabolism-shaping past never had to deal with long-lasting oversupply of sugars, so there was no pressure to evolve sugar-absorption blocking or removal mechanisms?

    Could it be that there are somewhat capable auto-regulation mechanisms to deal with overfeeding
    in protein and fats, but none that deal with an oversupply with simply carbs?

    *Evolutionary sidenote
    Archaeologists found that the human diet was very diverse and mostly based on fat, protein and vegetables in almost our whole past. Until 10.000 years ago, when agriculture started.
    Agriculture meant a sudden oversupply of calories, but mostly of carbohydrates.
    This shows in the health of pre-historic skeletons and death rate – with the advent of agriculture,
    -people suddenly had a higher disease and death rate, died much younger
    -teeth rotted away fast even in young humans, as shown in the skeletons un-buried
    -infant death skyrocketed
    -but population density and numbers skyrocketed, too:
    -with plenty of food from carbs, people got much sicker and diseased, even life spans reduced markedly,
    but with the vast new energy source of carbs from agriculture, total numbers of humans exploded
    -agriculture-using cultures displaced hunter-gatherers – if an area of land can sustain 30 times more
    people by agriculture than by hunting/gathering, then the 30:1 outnumbering will succeed over the
    hunter-gatherers in displacing them, even when the agriculture-fed population is sicker and weaker
    on the individual level

    It looks like we are the descendants of those who adapted to the sudden carb surge in our diet
    comparatively well – we still are sub-optimally healthy, but at least we are not dying off in droves
    like our ancestors with the advent of agriculture.
    Peoples exposed for longer times to the high-carb, “Western” diet should also be adopted better
    to it somewhat, which is what we find:
    I read that English and Central European people deal much better with the Western Diet than
    Asians, Pacific Islanders and Africans when suddenly exposed to it today – the latter get obese and sick
    much faster than Whites when moving into Europe or the USA than Whites who are used to this
    diet for a much longer time already.

    • Nick says:

      Interesting questions. The idea of us having not evolved to deal with sugar properly makes sense to not-even-lay-man me. And of course, us having developed civilisation, industry, and medicine effectively interrupted natural evolution.

    • James says:

      Brilliant comment, Montgomery. Makes a huge amount of sense. That’s why I love this website: not only is PD so eye-opening but so too can commentators. Probably only website for me where the comments are a “must read”.

    • P. D. Mangan says:

      Montgomery, great comment. Regarding losing weight on a diet that is not hypocaloric, that’s possible if the metabolism increases or, as you say, some of it isn’t absorbed. However, I believe this notion is disputed – I think even Michael Eades has said that it may not happen, though there is some evidence for it. The most likely reason people lose weight on low carb is through less hunger/increased satiety.

      There may be something to your theory. It’s accepted that health got worse when people started eating grains, and also that there are ethnic/racial differences in the degree to which people can handle carbs, especially grains and sugar. Like the Pacific Islanders.

      • peter connor says:

        Humans lost about 5 inches of height when they left a hunter/gatherer diet and went on a largely grain diet. That’s malnutrition. They also lost about 10 years in expected life span, and didn’t regain it until the 19th century. That’s pretty drastic, though part of the difference was doubtless public health related.. Maybe just going off grains and refined carbohydrates should be tried in the laboratory, though it would be an expensive diet.

    • Montgomery says:


      Speaking of a possible evolved mechanism to regulate homeostasis in a LCHF diet preventing fat-gain even
      with a somewhat hypercaloric diet – the mechanism needs not only to rely on changed patterns of absorption or excretion, it could very well be also purely energetic:

      (personal anecdote)
      This is my 1st winter on a strict LCHF diet.
      I do not want to sound ridiculous, but I found that I do not require a 2nd blanket at night for bed –
      before that I couldn’t sleep without it when temperatures went below 0°C outside; my room temperature
      should have staid the same as in the winters before, because I never use any heating in my bedroom.
      Not so this time – even at -14°C outside I could sleep well and subjectively warm without a 2nd blanket!

      What if a LCHF diet changes body temperature/ body heat generation/thermal equilibrium?
      It is known that thermoregulation kicks in when humans starve – the body temperature is lowered to
      conserve energy; this can be felt in people fasting/on a diet even in summer temperatures, they feel “cold” after few days of zero or near-zero calorie absorption (half a degree celsius or so can mean a lot of difference in
      energy use – after all, on average, humans use up around 2/3 of their food’s energy for thermogenesis).

      Caloric and thermal auto-regulation may be very different in diets with lots of and practically without of carbohydrates.

      Maybe we just get rid of some oversupply of fat/protein by generation of more body heat, while this
      process could be somehow hindered when lots of carbs are eaten?

      I remember a report about “old-living-style” Eskimos – their “youths” would eat Western foods for their taste,
      lots of carbs/cola/cake/etc. – but some older Eskimos, while also liking the sweet taste, rejected it, because they felt (IIRC) that this sweet food would make them feeling cold when hunting/living according to their
      culture for days in the arctic cold climate outside and insisted on eating only fish/zeal meat to be comfortable.

      • Montgomery says:


        (I misspelled zeal/seal, sorry)

        One a somewhat humorous side:
        Women are often overheard whining about too low a room-temperature in the cold season,
        while men feel fine.
        Thermoregulation in men and women is different, the latter burn less calories, supposedly
        because of their lower muscle mass.
        What if that explanation is wrong or only partially correct?
        Maybe, well, women snack more sweet stuff, pralines and such, than men, and because of that
        then suffer from a lower thermogenesis?

        Guys here with wife/girlfriend having to deal with that issue may be inclined to check this
        hypothesis experimentally: Just take your women on a strict zero-carb-high-fat diet for a couple
        of days and see how “warm” they feel without touching the room thermostat.

      • Montgomery says:

        I think that may be interesting in the light of my previous postings:

        “The Functional Food Centre at Oxford Brookes University conducted a study into the effects of chilli and medium-chain triglycerides (MCT) on Diet Induced Thermogenesis (DIT). They concluded that “adding chilli and MCT to meals increases DIT by over 50% which over time may accumulate to help induce weight loss and prevent weight gain or regain”.”

        I actually eat a lot of MCTs for personal health reasons, in the form of coconut fat, and, also
        for health reasons, vegetable stew with heavy doses of capsaicin/chilli added.
        The effect of the capsaicin can be felt immediately, but seems to wear of after a hour or so,
        at least subjectively.

        A 50% increase from eating this stuff, in terms of thermogenesis, would be a rather huge effect – not only for being more comfortable in icy climates, but also for fat-loss.

        From here:

        “Potential use in fighting obesity
        As a significant component of the metabolic rate, thermogenesis can potentially be stimulated to increase energy expenditure and fat oxidation. Thermogenics are commonly made up of ephedra, bitter orange, capsicum, ginger, guar gum, and pyruvate.[citation needed] Caffeine and EGCG, both found in green tea, may increase thermogenesis regulated by catecholamines such as norepinephrine.[7][verification needed] Researchers are also investigating the possibility of increasing the amount of brown adipose tissue in the body, a site of thermogenesis.[citation needed] Leptin infusions, being studied due to the leptin resistance seen in obesity, may boost metabolism by stimulating thermogenesis and also reduce hunger and appetite.[citation needed]
        Although bodybuilding formulations comprise the most common use of thermogenics, the supplements are entering the mainstream dieting industry.”

        It seems my ideas in my posts above are not novel, but actually established already.

        But the experiment with your women would still be interesting – fill them up with coconut fat and
        chili spice, restrict any carbs for a few days and see if they still crave higher indoor temperature and still have the legendary ice cold feet in bed. Maybe they will also loose weight?

    • Drifter says:

      Dr. Nally of the Ketotalk podcast spoke about the regulation of food intake in one of his podcasts in January and from what I remember, he believes there is a known mechanism where if insulin is low and the person’s fat-burning is up-regulated, then the body will only absorb the dietary fat it needs, at least for many people. Also, regarding body temperature, Dr. Fung has written a number of posts saying that one of the main benefits of LCHF and Fasting is that metabolic rate is maintained in comparison to a low-calorie eat-all-the-time-diet where the metabolic rate is suppressed, and this could account for elevated body temperature on LCHF.

    • Sam says:

      “…Maybe the fattening and illness-inducing effect of a high sugar diet is all about the fact that sugars cannot be non-absorbed or eliminated from metabolic pathways and have to be processed and stored, no matter what?…”

      Interesting and good thinking.

  9. nick says:

    Does this represent a change in your orientation? We still think autophagy is important to staying young, and this is facilitated by intermittent fasting, right?

    Yeah, feed animals crap, then feed others less crap.

  10. Hugh says:

    Like Nick above, I assume that you still think:

    1) fasting triggers autophagy
    2) autophagy is good for us as it cleans out damaged proteins (and neurons)
    3) the benefits of autophagy are separate from the benefits of good body composition, although people who practice intermittent fasting will tend to enjoy both types of benefit.

    It thus seems that the basic thesis behind (intermittent) fasting is intact.

    But I fully agree that the studies you mention appear badly flawed.

    • P. D. Mangan says:

      Nick and Hugh: Yes, I still think all 3 of Hugh’s points are valid. Regarding point 3, there’s an overlap between good body comp and benefits of autophagy, since those with good body comp are less likely to be eating all the time, have good insulin sensitivity, and exercise, which activates AMPK leading to autophagy.

      To clarify what I mean about the experiments I described, the people who did the fasting-mimicking diet undoubtedly benefited, as do animals undergoing CR. But the benefits might be just the ordinary ones of weight loss and less food. Profound anti-aging benefits are another story. Perhaps it’s a matter of diminishing returns; for instance, I know an older man, a reader here, who did a several-day-long fast. He’s already quite thin and seems to eat a healthy diet and lifts weights too. While he probably got some benefit from his fast, they likely are not in the same league as some benefits that have been described in the literature, since presumably he’s already healthy.

      So, yes, the basic thesis behind intermittent fasting still holds, but I think the Longo study didn’t really show that, and many (most?) CR experiments are flawed in the way that I described.

  11. Total Maga says:

    You could easily run experiments yourself at home. Mice are relatively short-lived.

    A bit off-topic, but I’d like to see some analysis as to why black men in particular seem to age so well. I know several in their fifties who could easily pass for 30. It seems they peak at some point, then go into rapid decline. I’m not alone in noticing this, but have not found much discussion. Possibly it’s related to hormone levels?

    Also, I’d like to read your thoughts about Methylene Blue.

    Thanks so much.

    • P. D. Mangan says:

      Hi Total Maga (great handle): I’d like to run some mouse experiments, and have thought about it, but there’s not a lot of glory in it, and zero money. For the same reason I gave up submitting papers to scientific journals – they got rejected, and no one is paying me to do it, and even if accepted, it would get me exactly nowhere.

      Black men have shorter lifespans than white men. My colleague Dr. Zacharski wrote a paper showing that black men have higher ferritin levels, and that may be one reason for racial disparities in health. Racial Health Disparities, and Variant Red Cell and Iron Homeostasis. Curiously, there’s a paradox where black people seem over-represented among the oldest old, such as the case of Richard Overton. Why that is, I don’t know.

      Methylene blue: I got some awhile back, only tried it once. More research is necessary.

      • peter connor says:

        Virtually all studies show that longevity is strongly positively correlated to IQ. It appears likely that this is a result of lower genetic load. In other words, a healthier body in general.
        How does this fit into the equation? It would certainly explain why black men have shorter lifespans–they aren’t as intelligent.

  12. Total Maga says:

    Mice: I was thinking more in terms of satisfying your own curiosity.

    Although black men have have shorter lifespans, there’s no escaping the fact the average black 50 year old ‘looks’ in much better condition than similarly aged whites. Many black men have little to no grey hair even in their late 60’s – which is extremely unusual in whites.

    Methylene blue: I’ve read some accounts of people experimenting with it on the “Ray Peat” forums, but it would be nice to get an overview and plain language explanation by someone respected and knowledgable.


    • Drifter says:

      People with darker skin tend to have little or no sun damage to their skin, however when living far from the equator, they also tend to have low Vitamin D levels, which would partially explain both of your observations.

  13. Drifter says:

    A related concern I’ve had about the CR studies is that they typically use an all-you-can-eat diet for the control group. Animals in captivity apparently tend to overeat, which makes sense given that unlimited food would almost never be available in the wild and the sheer boredom and depression of captivity could prompt over eating. It would be interesting to see if there was any significant benefit if the control group was limited to a reasonable amount of healthy food. Also, Paul Jaminet (in his series of blog posts on the Dangers of Zero Carb diets, I believe) has speculated, using Roy Walford as an example, that chronic unavailability of sufficient calories and/or glucose may suppress the immune systems of some people, which would not be a good thing.

  14. Ole says:

    A bit OT, but I think you can add many other studies to that list, P.D.

    The so-called health experts like Mr. Mercola, Michael Greger, Dr. Ornish etc. all use different scientific references. For example, I can easily find studies, which show that coconut oil increases LDL cholesterol, but if it suits me, I can just as easily find another study, which shows the opposite.

    The lack of consensus is actually highly damaging for a lot of people’s health, because many people go to the extremes. Take for example hard-core vegetarians, who eventually suffer from lack of B12, Taurine, Carnosine, Omega3 etc.

    The more extreme your diet is, the more likely it is your health will suffer…eventually.

    Or people on Dr Atkins diet, who eat so much protein that they damage their kidneys, not to mention overactivation of mTOR.

    Currently I’m sticking to the HVMLCMFMLP diet 🙂


    Knowing what a great fan you are of the vegetarian lifestyle, I think this one will make you smile.

    Dr. Adiel T-Oren suggests that we can go as low as 15-20 grams of protein pr. day, due to protein recycling:

  15. Sam says:

    Mangan I completely get your point about the flaws in diet studies.

    I’m sure you know this but the amount of calories in the fasting-mimicking diet is about the same, I think 800 calories a day, as people who get band surgery for obesity. This also cures their type II diabetes for some.

    While this is short term and not long diets, a 2008 presentation by Christopher Gardner for the Stanford School of Medicine talks about the different Diet books and a study he did to see which had the best outcome. Adkins won. I mentioned this because of the comment that people were getting protein positioning. I’m not sure this is true. People have lived for extended amounts of time on “just” meat and remained in good health.

    I remind you I’m not sure what the perfect diet is. The evidence seems quite contradictory to me.

    Native Eskimos had a huge fat/meat diet and it was observed that the Women aged extremely fast. I have no idea if it was all the fat and meat or it was that that particular genetic group aged quickly.

  16. Malcolm l Klein says:

    What appears to be novel in Valter Longo’s work is that the prolonged fasting is enough to stimulate autophagy to the point that organ weight (at least in mice) actually decreases significantly as well as white blood cell number. But then it is the refeeding phase that the real benefits are produced as it stimulates the regeneration of stem cells, so that for example in the case of white blood cells from aged animals, the immune cells recover from a nadir back to the higher levels of a youthful mouse, with a more youthful myeloid/lymphoid ratio.

    And in his latest paper he shows that 3 day fasts in mice can regenerate the pancreas beta cell to the point of reversing both type1 and type2 diabetes. He shows that early developmental genes are turned on indicating regeneration!

    While intermittent fasts of 14-20 hrs have clear benefits as well, they can’t produce this level of extreme deprivation followed by a rebounding recovery since it takes at least 24 hrs before glycogen is completely depleted and blood sugar really begins to drop significantly. I have tried both my own version of the 5 day mimicking diet and a 3 day water fast, and in both cases it wasn’t until the 3rd day that my blood sugar finally dropped into the 60s and ketones rose dramatically.

  17. Jorgan Proshnov says:

    Who cares about ‘longevity’ if you have to be (and look like) a mediocrity just to achieve it?

    Something that so many in this ‘longevity’ field seem to forget, is that it’s difficult to achieve significant muscle mass if you’re constantly limiting protein, limiting calories, (and thus also) limiting workouts.

    Seems like so many I see who are into this stuff are scrawny twerps.

  18. Georges says:

    i read very carefully your book “stop the clock”, and I am a regular reader of your blog that I appreciate very much. In your book, fasting and especially intermittent fasting play an important role in your anti-aging strategy because you explain that this is the only known measure that slows down aging in humans.

    On the other hand, I read this very interesting article on your blog (ANTI-AGING STUDIES ARE SERIOUSLY COMPROMISED) which explains that the studies on the effects of fasting on aging have a lot of statistical bias.

    Does this mean that for you, and despite what you have written in your book, it would be reasonable to question the role of fasting in the anti-aging strategy?

    • P. D. Mangan says:

      Hi Georges, good question. Calorie restriction has been shown to be the most robust, effective life extension intervention in lab animals, and intermittent fasting appears to be of equal or even greater efficacy. The question in my mind is, if a human ate an optimal diet, which I’m inclined to think is ketogenic, then does CR or IF add anything? Lab animals are typically fed the equivalent of processed food, and of course they are not identical in physiology to humans. Also, if a person is lean and muscular already, what do CR and IF add? My objection to Longo’s fasting-mimicking diet in humans is that many or most of the participants were overweight, and losing weight by any means, not just fasting, would presumably improve their health. And they did lose weight.

      Information that would help us understand the effectiveness of CR or IF is, what physiological mechanism causes life extension? The answer might be less fat mass, increased autophagy, lower insulin and IGF-1, upgrade to antioxidant defense mechanisms, or ketones. Or others. Or some combination.

      I still believe that intermittent fasting adds value to a low-carb or ketogenic diet, but perhaps not as much as we would like to think. Perhaps a good deal of the value of fasting lies in abstaining from bad food. I still continue to practice intermittent fasting regularly.

      • Georges says:

        Thank you for this quick and detailed answer.

        There is currently a lot of money that is invested in this field of research by countless startups, but also by giants like Calico (Google) or Chinese companies. The problem is that even if these companies were to make significant discoveries in this area, the paths explored (telomerases, genetic modifications, etc.) will not provide access to the largest number of people at an affordable cost.

        That’s why I think that the smartest solution for “average” people like me, could be a “Ray Kurzweil” solution, ie to use and potentiate the effect of known measures at this time (the ones you describe in your book) in order to wait the 20 or 30 years that will be needed before the discovery of effective and affordable genetic therapies in this area.

        I have a writing project on anti-aging strategies and I am currently in the research and gathering phase of scientific data. Would you be interested to do consulting for this project ? If yes, can i contact you in a private message?


        • P. D. Mangan says:

          The tech startup companies are of course seeking to make money (nothing wrong with that) but it seems as that is making them overlook some important interventions. For instance, rapamycin is available now and is a proven anti-aging drug. But there’s no money in it, since it’s generic.

          Georges, you can contact me via my contact page

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