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Fasting for CR Benefits?

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Adding to the question, whether the CR-effect in mice can be partly explained by fasting:

 

This review - though a little outdated (2013)  - summarizes a broad range of studies investigating mice metabolic responses to fasting from 4 hours to 48 hours:

https://journals.sagepub.com/doi/full/10.1177/0023677213501659

The issue isn't clear cut - certain metabolic markers are clearly changed after 12 hours of fasting. Others are not significantly different from 6 hours of fasting (fasting in MICE). In the Discussion section at the end of the paper the authors note, that the longest voluntary interval observed between meals was 5 hours and they note previously, that 4 hours constitute an "overnight"-fast in mice.

Another data-point is the bodyweight response - 12 hours of fasting in mice results in a 12% loss:

10.1177_0023677213501659-table4.jpeg

 

In comparison - in humans a much longer fast is needed to produce similar results; e.g.  in this study of monitored therapeutic starvation in obese individuals a 35 days to 41 days fasting lead to a 10,6% to 20,5% weight loss:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC535723/pdf/jcinvest00209-0174.pdf

 

So in terms of body weight loss a 12 hours fast in mice is similar to at least several weeks fasting in humans (and even more than one month in some individuals). Therefore I find it hard to just dismiss, that fasting can explain some of the effect of CR-mice even in those receiving a "spread-out"-CR over 12 hours.

 

Any thoughts or additional data points?

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Mike Lustgarten made a nice video (kudos Mike!) detailing part of the Nature Metabolism article we're discussing in this thread, namely the comparison between AL, diluted CR (i.e. CR without fasting), and standard one-meal-per-day CR:

 

He rightly points out that the part of the paper that compared CR against time-restricted ad libidum eating did not include lifespan data. So the strongest conclusion one might draw from this research is that CR may not be beneficial for longevity without fasting.

This is also the message one of the authors suggests in this popular press coverage of the study:

One takeaway for our species: people already cutting their daily calorie count by 20 or 30 per cent may want to consider limiting the time frame for eating those meals.

“If our findings apply to people, they may be losing some of the benefits of calorie restriction by spreading out their meals throughout the day,” he said.

The second part of this paper suggested the metabolic benefits of CR can be triggered in mice by fasting them for most of the day without restricting their calories. It does not address the question of whether the longevity benefits of CR can be attained in mice via fasting without CR.

--Dean

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1 hour ago, Guest said:

Another data-point is the bodyweight response - 12 hours of fasting in mice results in a 12% loss:

 [Table deleted]

In comparison - in humans a much longer fast is needed to produce similar results; e.g.  in this study of monitored therapeutic starvation in obese individuals a 35 days to 41 days fasting lead to a 10,6% to 20,5% weight loss:

So  in terms of body weight  loss a 12 hours fast in mice is similar to at least s everal  weeks fasting in humans (and even more than one month in  some individuals) .

Thanks Guest (and welcome to the CR Forums btw!).

Interesting findings comparing the impact of various fasting durations on mice and humans. But I wonder if the extrapolation you make is entirely fair.

As a personal anecdote, in the 19 hours between when I finish my last meal of the day (8am! :-)) and the next morning before I eat again, my weight drops by ~10 lbs, which is ~8% of my body weight. Obviously, since my weight is quite stable day-to-day, almost all of that weight loss is in the form of water and solid waste. But presumably that is also largely the case in mice during a long daily fast. 

This fact sheet about lab mice says:

"The average daily consumption of feed and water for an adult 25 g mouse is 3-5 g and 4 ml respectively."

Since the mice are relatively weight-stable from day to day, they must be pooping and peeing out that much too over the course of a day. Even ignoring the weight fluctuations resulting from the water it drinks and pees, 3-5g of daily food intake (and therefore at least that much poop, more if you consider that feces has a higher water content than rodent chow), would equate to at least an 8.5 - 20% daily drop in a mouse's body weight between the end of a mouse's one daily meal and just before the next day's meal. Note that an 8.5 - 20% weight loss range pretty closely matches the weight loss your table reports for a 24 to 48h fast in mice.

So it seems to me pretty specious to suggest that a 12-hour fast in mice equates to a fast of several weeks to a month in humans.

To really compare apples to apples it seems to me you'd have to measure how much fat mass + lean mass a mouse loses during a long daily fast (i.e. via autopsy) and compare that to the fat and lean mass lost by people during an extended fast. I'm skeptical that mice significantly deplete their fat stores or catabolize much of their muscle mass during a long daily fast, like you see in people who don't eat for a few weeks. But I could be wrong. 

Did (any of) the mouse studies in the review you posted perform that kind of assessment, or did they just measure change in total body weight before and after a period without food?

--Dean 

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Hi All!

This topic is basically discussed in Luigi's newest book, "The Path to Longevity".  Very brief summary:

(1) practice Calorie Restriction

(2) Eat at certain specific times, every day, with little or no eating between meal times.  Also, do the largest part of your eating early in the day.

Some possibilities:

one meal a day :  This is probably the best option.  Dean used to do this, but indicated recently that he doesn't anymore.

three meals a day: breakfast, lunch and dinner.  If so, your principle meals should be breakfast and lunch, with a very small, and early, dinner.  (My diet is like this.)

An aside:  This comes from a fairly old post, I think on the old CR mailing list:

The medieval scholar, Rabbi, and medical practitioner Maimonides said:

For breakfast, eat like a king.

For lunch, eat like a prince.

For dinner, eat like a peasant.

🙂

  --  Saul

 

 

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This early time restricted feeding (TRF) advice recently gained popularity because it was hypothesized to be in harmony with our circadian rhythm(s), and it was thought to have been supported by the much publicized Sutton et al., (2018) study that randomized men with prediabetes into an early TRF (6 hour feeding period, with dinner before 3 pm) or a control schedule (12 hour feeding period), and later crossed the groups over to the other schedule.  The early TRF significantly improved some aspects of cardiometabolic health, even without any weight loss.  My criticism of that study is that there were two potentially confounding variables (early versus later eating as well as a 6 versus 12 hour eating window) that differed in the experimental and control groups.  The study begs for a follow-up (which I haven't found) comparing only early versus late TRF.  Nonetheless, the results are noteworthy. 

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@ Dean

 

That is a valid point. Unfortunately it's no addressed in the review paper. The corresponding study for the 12 hour weight loss can be found here:

https://link.springer.com/article/10.1186/1471-2164-8-361

 

They are not analyzing the effect of intestinal content in assessing the body mass changes (though water is provided round the clock). however, they measure the change of mass of intestines after cleaning them of content (see methods section at the end). The result is displayed in this graph:

12864_2007_Article_1074_Fig2_HTML.jpg?as

Edit: the graph doesn't seem to load; it's Figure 2-A in the paper

So the intestines - after emptying their content - lost somewhat more percent of mass than the entire body in percent after 12 hours (relative to non-fasted mice and their empty intestines mass). I can only speculate, if this corresponds to the entire body mass loss (as no information is given on adjustment for the latter).

 

To complete the picture, here are some of the changes in the review paper for 12 hours fasts - noting, that for a range of parameters no data for 12 hours is included/available in the paper:

- leptin is at a low-stable level from 12 hours onwards

- unclear data in insulin level; but one study finds that after 12 hours there is low-stable level compared to 2-6 hours (but on didn't)

- contradictory results for gastric content; mice at 12 hours had similar gastric content as non-fasted mice - but at 4 and 8 hours their gastric content declined

- no change in cytochrome P-450 level at 12 hours (but at 24)

- mean time of initiation of first topor bouts: 13,3 hours ; initial drop of body temperature at 7-8 hours

- first changes in hepatoxic markers at 12 hours (and increasing from there on), but not at 6 hours

 

Edited by Guest

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Here is an interesting factoid about mice digestion from [1]. The mouse gut transit time from ingestion of colored food to excretion of the first colored poop pellet is a little over 6 hours. When I've made a similar measurement in the past, my gut transit time was a little over 24 hours. So by that scaling metric, the ratio of mouse fasting duration to human fasting duration would be ~4x. So a 21h fast in mice fed once per day would equate to a 3.5 day fast in people.

So your typical one-feeding-per-day mouse CR experiment equates to a person eating one (very big!) meal every 3.5 days for their entire adult lifespan. Good luck with that.

--Dean

--------------

[1] Kacmaz H, Alto A, Knutson K, et al. A simple automated approach to measure mouse whole gut transit. Neurogastroenterology & Motility. 2020;00:e13994. https://doi.org/10.1111/nmo.13994

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Let's assume ... the researchers were honest (did not cook the books, did not spike fasting mice water with metformin, etc); and competent (know how to use instruments, basic math skills, spreadsheets, etc)

AFAIK, thermogenesis -- in the new the Nat. Metab. study paper -- for fasting animals was not measured (?????). E.g. via a FLIR or IR scanner.

That is ... if ... the fasting animals remained at CR-like weights (as noted in paper); they consumed all their AL-equavalent rations (in the allotted time); did not defecate out extra calories.

========

WARNING!! ANECDOTAL SOME STUFF BELOW:

Wayyyyyyy back in the early days of CR, and definitely after I'd settled to my std. weight of 115-119 lbs, I do recall a few episodes of over-consumption (binging) that produced a heating/thermogenesis effect -- like intense exercising. Because the episodes were extremely uncommon, my weight did not budge. Unfortunately, these were not controlled experiments -- tickling the dragon is not good -- so no thermometer readings taken. But I ain't sure thermogenesis really manifests itself as "body temp". That'd be a fever ... which the organism does internally -- not exercise . Thermogenesis is a whole-body thang 😉
and ... Wikipedia does distinguish between various thermal states:

Quote

 

Depending on whether or not they are initiated through locomotion and intentional movement of the muscles, thermogenic processes can be classified as one of the following:

  • Exercise-associated thermogenesis (EAT)
  • Non-exercise activity thermogenesis (NEAT), energy expended for everything that is not sleeping, eating or sports-like exercise.[2]
  • Diet-induced thermogenesis (DIT)

 

  •  

Specific dynamic action (SDA) https://en.wikipedia.org/wiki/Thermic_effect_of_food

https://en.wikipedia.org/wiki/Thermogenesis

https://en.wikipedia.org/wiki/Fever

==========

Back to the fasting mice ... those EXTRA calories are goin' somewarez ... possibly unmeasured, non-fever thermal states.

Alas, thermal states do not explain the longevity effect of fasted animals  ... if and only if ... it was recorded accurately and reported honestly.

Edited by KHashmi316

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1 hour ago, KHashmi316 said:

That is ... if ... the fasting animals remained at CR-like weights (as noted in paper); they consumed all their AL-equavalent rations (in the allotted time); did not defecate out extra calories.

...

Back  to the fasting mice ... those EXTRA calories are goin' somewarez .. . possibly unmeasured, non-fever thermal states.

Um, did you read the paper?

As I said before and you can see from Figure 9 below, the time restricted AL-fed mice had about the same body fat (graph D) but maintained significantly more metabolically-active lean mass (graph C) than the CR mice, comparable in fact to the AL-fed mice. So their body weight was intermediate between the CR and AL mice (graph B). They also ate slightly less than the AL-fed mice, as shown in graph A. So your suspicions of fraud is unfounded and there really isn't any mystery about what happened to the extra calories the time restricted mice ate. When compared to the CR mice, the time restricted mice ate a lot more (within a 3h window each day), maintained more lean mass and so weighed more, and most importantly looked very similar in terms of metabolic health and gene expression at the end of the 16 week experiment.

Since we don't have lifespan data on the time restricted mice, the more interesting and informative portion of this body of research was the other part, where mice that consumed 30% fewer calories than AL mice but that were allowed to graze whenever they wished (like is typical for mice) lived shorter lives than even the AL mice, strongly suggesting that the longevity benefits mice enjoy from a typical 30% CR experiment may be largely a side effect of the big time gap between meals, not the reduced calories per se.

--Dean    

Screenshot_20211023-174625_Chrome.jpg

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14 minutes ago, Dean Pomerleau said:

So their body weight was intermediate between the CR and AL mice (graph B)

Are you looking at the error bar SPAN for the AL (white)? Dunno ... dude ...  to me eyez ... TR.al and CR look closer to each other in the final couple o' weeks. And then there is BF (fat mass?). Low BF (fat mass) may be more important than scale (mostly muscle???)  weight. And this my relate to possibly unmeasured, non-fever thermal states.

ANECDOTE: As reported on the list decades ago, my own WBC, Testosterone, and Body Temp did not undergo much "CR" improvements until my BF went to 1-2% (Tanita measured).

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On 10/23/2021 at 6:14 PM, Dean Pomerleau said:

... the more interesting and informative portion of this body of research was the other part, where mice that consumed 30% fewer calories than AL mice but that were allowed to graze whenever they wished (like is typical for mice) lived shorter lives than even the AL mice, strongly suggesting that the longevity benefits mice enjoy from a typical 30% CR experiment may be largely a side effect of the big time gap between meals, not the reduced calories per se.

--Dean    

One aspect of this portion of the study that I was dubious about was the method the researchers used to allow mice to eat an ad lib volume of food over the course of the day but get only 70% of the calories of mice given continuous access to regular rodent chow. The method they used was to dilute the food with indigestible cellulose, tricking the mice into feeling satiated while ingesting fewer calories spread out over the day.

While many of us happen to eat a very high fiber diet like this, and while the researchers did measurement to verify the extra fiber wasn't interfering with calorie absorption,  the study's dilution strategy still seemed to me like it might create confounders by adding (mostly) indigestible fiber to the guts of the dilution-fed mice.

That is until I came across this 2020 study [1] while looking into mouse gut transit time. It looked at what mice subjected to 25% CR ate over the course of the day besides their food. It turns out in addition to eating their own feces (yuk!), the mice consumed between 0.6g and 1.5g of their fibrous bedding per day, depending on the bedding material (wood vs cellulose vs corncobs). This is a significant fraction (up to half!) of their daily food intake by weight, which you'll recall from my previous post is 3-5g / day for AL-fed mice.

In other words, CR mice fed rodent chow once per day naturally graze on their cage bedding during the 20+ hours that their food hopper is empty. Given this fact, it would seem that the diluted CR group and the "regular" CR group in the study we are discussing were very likely munching on (largely) indigestible fiber throughout the day. The only difference was that the diluted CR group were also ingesting calories throughout the day along with that fiber, while the "regular" CR group was only ingesting a substantive number of absorbable calories over a short window of time in the morning and eating only fiber the rest of the day.

This makes me less suspicious of the dilution paradigm and more inclined to give credence to the finding that eating one's calories outside a relatively narrow window of time during the day (preferable in the morning given the results from time restricted eating studies in humans that are discussed in the paper) is not a very good idea, whether one practices CR or not.

--Dean

-------------

[1] Gregor, A., Fragner, L., Trajanoski, S. et al. Cage bedding modifies metabolic and gut microbiota profiles in mouse studies applying dietary restriction. Sci Rep 10, 20835 (2020). https://doi.org/10.1038/s41598-020-77831-3 Free full text: https://www.nature.com/articles/s41598-020-77831-3

 

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1 hour ago, KHashmi316 said:

And this m[a]y relate to possibly unmeasured, non-fever thermal states.

You may be surprised to hear that you won't find me arguing against this hypothesis.

In fact, after thinking about it, that may be exactly what's happening. As in almost all CR rodent experiments, these mice were housed at 70F (20-22C) temperature, which is many degrees below thermal neutrality for mice (~80F), which I discussed (ad nauseum) in the cold exposure thread.

So if you are saying what I think you are saying, namely that feeding mice an AL amount of food in a narrow window of time and allowing them to burn off the extra via cold-induced thermogenesis during their long daily fasting period confers on them the metabolic, gene expression and potentially longevity benefits of CR, you won't get any argument from me. In fact that is a pretty good summary of the entire 500 pages of arguments and evidence on cold exposure thread!

It is unfortunate that the researchers didn't measure thermogenic brown adipose tissue (BAT) in the three groups of mice. I would bet good money based on evidence presented in the cold exposure thread that BAT was elevated in the time restricted AL-fed mice relative to the other two groups.

And note the opposite effect may explain the other arm of the experiment with the diluted CR mice dying earlier than even the AL mice. With 30% fewer calories than AL and no digestive downtime, the diluted CR mice may have been particularly bad at maintaining BAT and therefore generating heat, worse than either the AL-fed or the regular CR mice. As a result their health and longevity suffered despite eating fewer calories.

But if that is the case (i.e. you can get the benefits of CR without the calorie deprivation if you eat a lot in a narrow window of time and burn the excess off via thermogenesis during the rest of the day) aren't you undermining your own (and Michael's) "Calories, Calories, Calories" mantra?

--Dean

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Thanks so much for sharing your extensive expertise, Dean.  I've checked out the time restricted eating human studies that you mentioned "...give credence to the finding that eating one's calories outside a relatively narrow window of time during the day (preferable in the morning given the results of time restricted eating studies in humans that are discussed in the paper) is not a very good idea, whether one practices CR or not."  The time restricted eating studies were comparing breakfast versus dinner OMAD (Cornelisson, Stote, and Carlson) with OMAD's necessarily consequent high glycemic loads, or looked at subjects with type 2 diabetes (Arnason, Bowen, and Mansell).  I believe that the evidence at this point in favor of early versus late time restricted eating per se is preliminary at best.  Did I miss something? 

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16 minutes ago, Brian Valerie said:

I believe that the evidence at this point in favor of early versus late time restricted eating per se is preliminary at best.  Did I miss something? 

That is most of the direct evidence I know of in favor of morning vs evening time restricted eating in people. But I haven't looked into the evidence lately.

If the hypothesis I just outlined is true, namely that BAT and cold-induced thermogenesis may be important mediators for the apparent benefits of time restricted eating, than I would suggest further support for morning (vs evening) eating stems from the circadian rhythm of thermogenesis in humans, which is naturally high during the day and low at night. 

--Dean 

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The literature on all this is rather elusive:

- it seems this is the first CR study that had a true adlib-feeding pattern for the CR mice; otherwise all CR studies in mice also used fasting (from 12 to 23 hours), which makes it so challenging to disentangle

- as you are pointing out, there are other metabolic influences in the background which again complicates things

 

So what are the actionable consequences - assuming for the point of argument that the findings are correct?

1. If the CR-effect in mice is indeed predominantly a fasting effect, it appears there is not much to translate. The equivalent fasting periods in humans - at least a couple of days every week, if not even 6 days a week - are very impractical to implement.

2. If its a temperature effect - is this really something that applies to humans? Also again considering the body temperature changes of mice. Mice are species that can and do undergo torpor and after 7-8 hours of fasting demonstrate a notable decline in basal body temperature. That is clearly not seen in humans after short fast of 1 or 2 days.

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On 10/22/2021 at 2:19 PM, KHashmi317 said:

methinks merecall Michael Rae having disputed much of fasting .... anyone have access to the legacy posts? 

I finally thought to search these forums for Michael's perspective on fasting. In this thread from 2015:

Michael makes the case based on the evidence available at the time that any observed benefits of intermittent fasting / time-restricted feeding results from calorie restriction and that intermittent fasting / time-restricted feeding in the absence of calorie restriction won't confer much benefit.

Of course I can't speak for what he would say about the latest study we are discussing here. But if I had to guess, I think Michael would say:

1) The apparent benefits of ad-lib calorie intake within a limited 3h period each day were only shown to manifest as improved biomarkers. Improved biomarkers don't necessarily imply extended lifespan as other studies he cites in that thread have demonstrated.

2) The reduced lifespan of mice who consumed 30% fewer calories than AL in the form of fiber-diluted food eaten nearly continuously throughout the day may have either a) thrown off their circadian rhythm because in order to get enough calories they probably had to eat well into the part of the day when they are normally dormant and/or b) simply demonstrated that nearly continuous snacking throughout the day is unhealthy, a point he makes in one of the later posts in that thread. That is, you should give your body some time between meals where it isn't processing food, but especially long such periods aren't much (if any) better than shortish such periods, as long as you are calorie-restricted.

It would certainly be interesting to hear his perspective on the evidence in favor of intermittent fasting and time-restricted feeding that has accumulated in the six years since he last posted to that thread. Unfortunately I don't expect we'll hear from him since he's probably quite busy dealing with the turmoil at the SENS Foundation...

--Dean

 

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Been jottin' down notes on this topic ... the ol' fashioned way ... writin' on the back o' da 'velope 😉

The "findings" in the new Nat. Metab. -- if orig. research was well designed and executed, and honestly / accurately reported -- is an interestin' 'rithmetic problem. Where'd dem calories go? That said ... With the 'velope in hand ...  I'm just gonna go  rando on you guys ...

(1) As Dean suggested earlier,  too bad that they killed ALL the animals at 16 weeks. So no MAX LS data 😞

(2) About Fig. 9B (the "on the scale" weight, me 'sumes) ... hmmm ... for the fasted animals, I wonder how much of that is water weight? I.e. an over-accumulation that's not be pissed out as normal (ends up as structural water, between   muscles -- "water gain"). If the mice were in their cage, FASTED, bored, they may have filled their growlin' bellies with water. And/or mice have to LOOK plump and normal/attractive in front of their own kind. And/or having a certain BODY MASS is important for the animal's normal movements (dynamics). And/or looking bigger/stronger may scare off some predators. Etc. The AL and TR.al  SCALE weights were somewhat similar in the first several weeks ... and then mother nature figures out the new  feeding schedule and adjusts to "normal" water drinking ... hence that diversion of weights towards the final weeks ??????????

(3) Gut microbes' role in all this ... "changes in digestive efficiency, or the efficiency of the gastrointestinal tract to extract calories from ingested food, is a major contributor to energy balance." [1]

How efficient are these bugs for processing food for TR.al -- especially given that fasting is wayyyyyy abnormal for "grazers" like mice? Could they -- gut bugs --  feed themselves FIRST, before RATIONING out the rest for their host --- in a rush job that is inefficient? So .... the big   TR.al fasted meals are broken down by the gut bugs ... but not so, efficiently / completely ... so some "calories" excreted,but not in components that a bomb calometer would pick up.

[1] The Gut Microbiome, Energy Homeostasis, and Implications for Hypertension

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773096/

 

Edited by KHashmi316

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Also meant to include this study/paper in my last post ...

Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127503/

Quote

Background: Studies in mice indicate that the gut microbiome influences both sides of the energy-balance equation by contributing to nutrient absorption and regulating host genes that affect adiposity. However, it remains uncertain as to what extent gut microbiota are an important regulator of nutrient absorption in humans.

Objective: With the use of a carefully monitored inpatient study cohort, we tested how gut bacterial community structure is affected by altering the nutrient load in lean and obese individuals and whether their microbiota are correlated with the efficiency of dietary energy harvest.

[...]

 

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Just to add in favor of CR:

 

there have been some mice studies, where the researchers tested different levels of CR under similar conditions (mouse strain, laboratory conditions, feed etc.). Generally a more stringent level of CR lead to better lifespan-effects. This indicates, that calories probably play some role - it would be interesting to look up, if the feeding-schedule in those were identical.

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I remember an old post made on the old CR List.  The poster wrote:

I just looked in the mirror.  I am not a mouse!

  😀

    --  Saul

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This new study in Nature Communications [1] found that tumor growth and metastasis in a mouse model of breast cancer were better controlled by daily, time-restricted feeding (20% CR, one meal per day) than in an isocaloric fasting mimetic diet (FMD) regime which consisted of cycles of 10 days with no restriction followed by 4 days of heavy restriction (30% of ad lib calories). They also found that a specially formulated mouse version of Longo's FMD diet (low carb & protein, high fat) was no better than an isocaloric amount of standard rodent chow when it came to preventing cancer growth.

Of course as discussed earlier, once-per-day feeding in mice potentially equates to a 3-4 day fast between meals in humans, and the 10:4 FMD regime used here might equate to a month of no restriction followed by two weeks of eating 3000-4000 calories as a single meal once over 4 days. So it's not clear how relevant these results are for humans.

--Dean

--------------

[1] Pomatto-Watson, L.C.D., Bodogai, M., Bosompra, O. et al. Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition. Nat Commun 12, 6201 (2021). https://doi.org/10.1038/s41467-021-26431-4

Abstract
Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR’s stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.

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