An intermittent fasting pathway to longevity

Fasting (intermittent, IF, or alternate day, ADF) may be the newest diet craze rivaling calorie restriction (CR) to increase longevity and improve health. Recent reports have shown that fasting diets can confer health benefits similar to (or even greater than) those of chronic calorie restriction (CR), without reducing the number of calories consumed relative to an ad libitum diet. The molecular mechanisms underlying the IF diet induced longevity are not well understood.

Honjoh et. al. established a fasting diet regimen in C. elegans to study molecular pathways involved in fasting induced longevity. They found that alternate day fasting (ADF) had a 40.4% increase in lifespan, and intermittent fasting (IF: every two days) had a 56.6% increase in lifespan over ad libitum fed worms. In contrast, chronic CR only increased lifespan by an average of 13.2%.

CR and IF may have similar effects on lifespan, but results reported in this paper indicate that signals in each of these processes are distinct. skn-1 and pha-4 have been shown to be essential genes in the CR longevity phenotype, but are dispensable in IF longevity.

Two proteins that were found to be important in this model of IF induced longevity are RHEB-1 (Ras homologue enriched in brain) and it’s downstream target, TOR (target of rapamycin). Inactivating either of these genes suppressed the longevity of worms on the IF diet, adding support to the role RHEB and TOR proteins play in influencing lifespan. Interestingly, inactivation of RHEB-1 did not mimic IF longevity, instead it recapitulated CR in lifespan increase and target gene activation. Thus, the authors conclude that RHEB-1 has a dual role in lifespan regulation.

Signaling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans.

RHEB-1 exerts its effects in part by the insulin/insulin growth factor (IGF)-like signaling effector DAF-16 in IF. Our analyses demonstrate that most fasting-induced upregulated genes require RHEB-1 function for their induction, and that RHEB-1 and TOR signaling are required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signaling by RHEB-1 in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signaling pathway.

The authors performed a microarray on fasted worms with or without RHEB-1 or TOR RNAi to identify gene expression changes. They found that the majority of genes that were upregulated as a result of fasting were dependent on RHEB-1 and TOR (100 out of 112 genes and 94 out of 112, respectively). RNAi of either RHEB-1 or TOR suppressed the induction of these genes in fasting. Through further analyses, hsp-12.6 (the C. elegans orthologue of αB-crytallin) and ins-7 (insulin-like peptide 7) were identified as downstream targets of RHEB-1 and TOR and are critical for mediating the IF-induced longevity phenotype.

It will be important to follow up on these findings, which elucidate the molecular pathways behind longevity diets, to determine how different diets overlap (or are distinguished) at the molecular level – especially considering that it seems improbable that people will willingly embrace a lifelong restricted diet to improve their health and lifespan. Understanding these pathways and factors involved will hopefully advance our ability to develop pharmaceuticals to mimic the benefits observed in these longevity diets.

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34 comments

  1. Very good post. I found this paper quite interesting – but a two days fast – that will be tough, and this is someone that routinely does 3 days a week of 20-24 hour fasts.

    There has been a number of studies in mice and rats using every other day fasting (EODF) and it improves lifespan (but far as I remember in the same range as CR). But there has been less longevity studies using EODF compared to CR.

    thanks again for a well done blog post

  2. Funny science should uncover such evidence 1400 years after Prophet Muhammed (peace be upon him) instructed us of its benefits. Specifically that the best fast is the fast of Prophet David and that Prophet David fasted every alternate day, ADF.

    Western anti-Islam Guru’s are quick to qoute the Hadith (sayings of Prophet Muhammad) out of context; let’s see you wriggle out of this one…

    Cheers.

  3. Sorry if I sounded condescending in the above post.

    Humility is not my strong point; I was reminded of George Bernad Shaw who said Islam is the best religion but Muslims terrible adherants. We are all human and to err is human. =)

    Seriously, if anyone would like references to this particualar Hadith or any other strong Hadith for that matter, please feel free to check them out for yourself by Googling: MSA-USC Hadith Database.

    Cheers.

  4. Liz,
    Very interesting post, but I go along with Larry. ADF is unambiguous, but the phrase Intermittent Fasting as used in this article is confusing. Exactly how many days of eating and fasting constitute “Intermittent Fasting”? I engage in two one-day fasts (40 hours each) and one two-day fast (64 hours) with 8-hour feast periods per week. Thanks

  5. Regarding the IF schedule- I agree that the use is confusing. The author’s state simply they used an “every two day fasting” and in figure 1 the light blue arrows (representing the fed days) appear to be the same size as the two day arrow, and the pink dotted lines (fasted days) are the same size as the arrows. That made me think in this situation it is a 2 day feed, 2 day fast- but since I am unsure I will email the corresponding author and report back when I know for sure. Thanks!

  6. Dude, come on, this is a scientific discussion. If the odds are right, anything is possible – take atoms for instance. Atoms (whose size is smaller than 1/1000th the width of a peice of paper) are themselves joined together to create us, the world, and galaxies… I know that’s big odds of this all coming out of a chance; a roll of the dice so to speak. Nevertheless, our resident scientist can answer give you the exact quantitative number, I am sure.

  7. Insteresting article.
    Regarding the duration of fast for the ADF: if the fast lasts longer than 12 hours, I find it rather cumbersome.
    I am interested in learning a few more details on the exact regiment the specimen have undergone in this study.

  8. So, I’m wondering if this has any applications to nutritional studies, particularly in populations where involuntary fasting may have been common. I’m kind of wondering if the so called “China Study” could be considered invalid with the long periods of famine that the population endured. Also, if we were to examine centenarians would we discover any socio-economic biases (endemic poverty at some point, depression/ww2 era starvation, embargoed nations).

    If there is a set of genes which are being activated across all species it would be interesting to see if centenarians overexpress these. Cool post, btw.

  9. Hi,

    when I read the paper when it first came out as an express article I too was confused on what exact fasting method they were using. I wrote the authors but did not get a reply. But like Liz from looking at the diagrams it seems it was a 2 day fast followed by 2 day of eating.

    Lance, as for ‘natural’ studies of starvation you must remember that any form of dietary restriction must also include ‘adequate nutrition’ which under most severe cases that have happened to humans they are far below adequate nutrition in terms of vitamins, etc.

  10. So the correct quote I believe is “Even a stopped clock tells the right time twice a day”, from the movie “Withnail and I”, a most excellent film.

    Does alternate night fasting count? I think I could do that better than day fasting, since I kind of already fast at night anyway?

  11. V — as much as I love W&I and respect the creative talents of Bruce Robinson, I believe the concept predates the film by many decades, and comes in many flavors. My best efforts on the internet reveal no definitive originator. The film quote is just one of many versions of the expression.

    I had considered “even a blind pig finds an acorn once in a while,” but didn’t want to unduly offend our Muslim friend who commented above. Either expression is certainly relevant to the “revelation” that — very occasionally — scriptural sources contain useful information. The problem, of course, is that they’re mostly wrong the rest of the time.

  12. Years ago I read a result in a French journal published circa 1965 that claimed that lifespan of lab animals (mice, I think) was extended by an ad libitum diet with mildly reduced nutritional content. I am unaware of any study that tried to corroborate it.

    I wonder whether caloric reduction is sometimes credited when reduction of some other factor should be. For example, C.elegans lives longer with a diet lacking Coenzyme Q –
    http://www.sciencemag.org/cgi/content/abstract/295/5552/120

    Is it conceivable that alternate day restriction of some nutrient(s) in an ad libitum diet would have similar results?

  13. This whole EOD thing is a biogerontological urban legend. I can’t speak for the Drosophila finding — CR in fruit flies is a bit of a puzzle in itself, which I doubt has much to do with the mammalian equivalent — but in rodents, contrary to what’s often claimed, the evidence clearly shows that IF is only effective to the extent that it results in an actual reduction in Calories consumed — and even at that, it’s a riskier and/or less effective way to implement CR. See:

    http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18599363
    (“Dietary restriction” here was IF without concomitant CR).

    … and:

    http://www.imminst.org/forum/index.php?showtopic=27757

    … and embedded links. Can we please stop talking about it?

  14. @Michael:
    I am personally devastated that someone would term my adopted dietary/nutritional regime “a biogerontological urban legend” ….NOT!!! I realize that a person’s results are considered anecdotal but EOD/IF has provided me with outstanding results in my pursuit of health/longevity. I also know that due to the expense, time, and effort required for double-blind controlled studies there are many questions in human diet and nutrition where we may never have total resolution of some questions. It is somewhat startling that someone with the Methuselah Foundation would state that we should not examine and discuss unproven and unsettled controversies. I suggest that the examination and exchange of new and unproven ideas continue enthusiastically and unimpeded!
    Thank you for the opportunity to comment.

  15. All — respectfully — this is far from a solved problem within the field, so let’s please not talk about it like it is.

    As always, as scientists, we’re at our best when we keep our criticisms close to the data, and stay away from blanket characterizations (Michael) or personal anecdotes (Faster).

    New information is emerging all the time on most subjects, and on this topic in particular. There’s been recent renewed interest in IF; this paper, other recent studies blogged here, and work currently in progress have provided evidence that there are genetic mechanisms operating in IF that are distinct from CR — and there are a lot of people working on figuring out the details.

    Whether or not the fly and worm results bear out in mouse is an open question, one that will only be answered by experiment. In order to figure that out, step 1 is to figure out those mechanisms; step 2 is to identify orthologous pathways in mammals, and step 3 is to investigate the role of those pathways in mammalian longevity. We can accomplish none of those goals from our armchairs.

    It’s worth keeping in mind that the invertebrate results might not bear out in a mirror-image manner in mammals; this is not to say that studying IF’s mechanisms in fly and worm won’t give us important information about mammalian aging. Different organisms’ lifespans are likely subject to different rate-limiting phenomena; a given mechanism may not appear to influence lifespan in a wildtype mammal, but may be revealed to be more important when the primary limitation on lifespan is removed.

    Is it premature to advocate IF in humans? In my opinion, yes. But is it worth talking about, and studying? Absolutely.

    In conversations on any topic, the idea that past studies have been so definitive as to warrant a permanent conversational blackout is more than a little silly. Revisitation of previous results in light of new findings or new paradigms is an important, perhaps essential, part of the scientific process.

    So no, let’s not stop talking about it. And I’ll thank the community members for not asking us or one another to do so in the future.

  16. Ouroboros,

    thanks for giving us a proper perspective on this issue (or any issue in science). I agree, there is still far more we need to study before we can even think of making some semi-conclusions.

    to more research, to more knowledge.

    thanks

    Ward

  17. Hi Liz,

    It’s been a month since this blog entry originally posted so I was wondering if you had gotten any clarification of the exact duration of the feed/fast periods that were used in this experiment. If not, I will settle for the two comments (one by yourself) speculating on their lengths. Thanks you for an interesting blogpost.

  18. Hi Faster,

    I am sorry to report that I have not heard back from the authors.
    I guess we will all have to settle for the speculation.

    Liz 🙂

  19. I find Faster’s regimen intriguing. Because of differences in metabolic rate between rats and humans, I have assumed that the ADF routine would have a greater longevity impact on rats than on humans. Going over 2 1/2 days without eating might be long enough in humans. Mattson’s results that rats on ADF could maintain body weight suggests that weight loss is not necessarily required. As for going 64 hours without eating, it seems like it ought to be possible if one ramps up slowly, since I suspect it would increase glycogen and fat storage during periods of feasting.
    The key of course is the trigger point for inducing the protective effect, which probably will vary for different proteins involved in the process.

  20. Can anyone help me get in touch with
    Faster (6yrs+)?
    I would like to ask him/her about their fasting regimen.

  21. “Alternate-day fasting and chronic disease prevention: a review of human and animal trials”

    Very good review. Sheds quite a bit of light on the subject, and totally invalidates Michael’s comments above.

  22. We have just published a new evolutionary explanation for the effects of fasting on longevity, in PLoS One. Discussion on my website.

  23. Not sure how many go for IF are aiming for longevity. It looks a little difficult to proof it on human being. But in the short term I could see benefits such as weight loss, indigestion relieve and higher level of concentration at work. I do 24-hr IF three to four time a week.

    Anna

  24. What a great website, just discovered it.
    I have been doing adf for a few years now based on the method given by
    http://www.johnsonupdaydowndaydiet.com/ which suggests that cutting back to 25% of normal on the fast day is enough to stimulate the genetic effects.
    I “fast” for 36 hours which is also meant to be the time need by the body to switch to a fasting mode (anecdotal)
    I would be interested in hearing other peoples experience. But mine has been that i have lost weight, and feel quite good on the diet. It certainly has taught me a lot about my eating habits and sharpened up my bodies sensitivity.

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