55 replies to this topic

[Michael]

All:

In recent posts, I've documented that alternate-day fasting (IF/EOD) without a concomitant reduction in Calories consumed fails to retard aging or extend lifespan in rodents. More recently, I reviewed evidence that compressed-window daily eating and alternate-day fasting does not provide the benefits of Calorie restriction in humans.

I was recently pointed to an old review ((4) -- published before the clear refutation in (7)) that tried to make the case that alternate-day fasting (= "intermittent fasting" (IF) = "Every Other Day feeding" (EOD)), without accompanying reductions in Calorie intake, would indeed provide the benefits of CR:

It was assumed for many years that the physiological responses to [CR and EOD] paradigms were due exclusively to a net decrease in energy intake. Recently, however, it was found that some species and strains of laboratory animals, when fed AL every other day, are capable of gorging so that their net weekly intake is not greatly decreased. Despite having only a small deficit in energy intake relative to control levels, however, these animals experience enhanced longevity and stress resistance is enhanced in comparison to AL controls as much in animals enduring daily restriction of diet. These observations warrant renewed interest in this paradigm and suggest that comparisons of the paradigms and their effects can be used to determine which factors are critical to the beneficial effects of caloric restriction ...

A particularly informative study of the effects of EOD feeding on mice of different genotypes was published in 1990 [1]. In that study it was reported that male A/J mice introduced as adults (6 or 10 months of age) to an EOD diet, did not decrease bodyweight and did not show any benefit in terms of longevity. In fact, those in the EOD group died early. In contrast, the maximum life span of male C57BL/6J mice begun on EOD at any age was increased. They also showed little change in bodyweight. (As noted elsewhere in this review, this is now known to be due to their ability to gorge when provided with food [5].) The F1 cross of the two strains responded well to EOD in terms of life span, but were unable to maintain bodyweight. In another study on the same mice, both EOD and LD groups were included. EOD feeding increased maximum life span by 56%, LD by 36% [2]. In contrast to these rather dramatic life span extensions, a mere 11% increase was seen in an earlier study [3]. (4)

I read that article when it was hot off the press, and later papers by the same authors (and Mark Mattson, another prominent EOD researcher). I thought at the time that the evidence strongly argued that their thesis would not pan out, for reasons that I explain here. But in looking back at this particular review, I see that even then, the analysis in (4) was deeply flawed. This post documents these errors of fact and reasoning; apologies for partially reprising arguments and analysis given in the just-linked post.

First, again, actual food intake was not measured in any of the lifespan studies cited (except for (3) -- and as we'll see, it's misused here), so the basis for the argument rests on first assuming that we can equate body weight with degree of effective CR, and then for the C57BL/6J mice combining (on the one hand) the LS results from (respectively) Goodrick, and from Ingram & Reynolds, with (on the other hand) the short-term Anson 2003 study, conducted many years later, and in another lab, in which this strain was indeed been found to gorge enough to make EOD basically isocaloric to AL.

Now, let's look at the analysis. Anson et al (4) rightly says that in (1), "A/J mice introduced as adults (6 or 10 months of age) to an EOD diet, did not decrease bodyweight [see image below] and did not show any benefit in terms of longevity. In fact, those in the EOD group died early." So in this strain, EOD let to no CR, and not only didn't lengthen LS, but shortened it.

They (4) also say, correctly, that in (1) "The F1 cross of the two strains responded well to EOD in terms of life span, but were unable to maintain bodyweight" -- ie, they lost a lot of weight (see the figure below). So for this strain, EOD apparently did lead to de facto CR -- and when you impose CR, you extend life.

But then (4) says that in the same study (1), "In contrast, the maximum life span of male C57BL/6J mice begun on EOD at any age was increased. They also showed little change in bodyweight. (As noted elsewhere in this review, this is now known to be due to their ability to gorge when provided with food; Anson et al. 2003.)"

This analysis is thus by its nature somewhat inductive, and only make sense if, as Anson et al (4) claims, (a) AL vs EOD feeding C57BL/6J mice in (1) "showed little change in bodyweight" and (b) Goodrick's mice in (1)responded to EOD as Anson's (5) did 13 years later.

But there are a lot of problems with this. First, to simply note that "the maximum life span of male C57BL/6J mice begun on EOD at any age was increased" in (1) ignores the fact that the mean LS of these mice was actually unaffected. How do you get an increase in max LS with no effect on the cohort as a whole? By having a lot of mice dying prematurely, but with the last 20% of the EOD mice still surviving at the end living sufficiently longer than the equivalent quintile of ALers to make it a wash for the average of the entire group. By contrast, with normal CR, you see an extension throughout the survival curve.

Moreover, Anson et al's (4) claim that AL vs EOD feeding to this strain in adults in (1) "showed little change in bodyweight" is questionable: they don't give the actual numbers, but the authors themselves assert that "With respect to diet effects, again the EOD regimen was effective in significantly reducing body weight among C57 and F1 genotypes at every survival quartile beyond baseline." Here are the body weight curve for animals of each strain, at each age of initiation:

As you can see, the EOD C57 and F1 hybrid mice in this study actually did lose a significant amount of weight -- and, notably, this body weight appeared to be tied to the LS gain in the longest-lived 20%, in whom there was a full 15% body weight loss, matching up with a LS gain 6%:

(Be careful when looking at these Figures. The dashed line is the controls; the solid line is the EOD group). This is not too far off from what you'd expect from 'regular' CR, and if anything is slightly poorer. For instance, in (6), when 25% CR was initiated at a slightly older age (12 mo instead of 10), it "lowered body weight by 26% and increased maximum life span by ~15%."

So, in (1), we have 3 strains put on EOD as adults. One (A/J) didn't undergo any CR as a result, and it shortened their lives; one did undergo CR, and it lengthened their lives; and one apparently underwent relatively slight CR, and it shortened the life of most animals, but the few that struggled through an initial period of high risk enjoyed a relatively slight lifespan increase in the end. Does this sound like a vote of confidence for EOD eating? No: it shows that whatever benefits ensue come from CR, and not very safely.

Next we have Anson et al(4)'s analysis of (2), which is, simply, wrong. They claim that in C57BL/6 mice in this study "EOD feeding increased maximum life span by 56%, LD by 36%" -- but in fact, these numbers come from (2)'s Table 3, which instead shows 56% and 36% increases in mean LS. Unfortunately, (2) doesn't report maximum LS data at all; moreover, because they don't give the absolute numbers, we don't know how long-lived the controls are even on average: the strain was healthy, but certainly lots of people have managed to create bogus "life extension" effects even with healthy strains by poor housing, veterinary, or other practices, and for all we know the colony had a poor diet, an infectious epidemic, etc, against which EOD protected them in a way that is of no relevance to aging of man or mouse.

And then there's (3), of which the Anson et al review (4) says, "In contrast to these rather dramatic life span extensions, a mere 11% increase was seen in an earlier study [3]". True enough -- and that's about as much information as the abstract gives us. But for Anson to note this without further comment, in the midst of an argument that C57BL/6J mice on EOD show "little change in bodyweight" which is "now known to be due to their ability to gorge when provided with food" (again, based on the results of (5), rather than the original experiments themselves), is either totally dishonest or involved making assertions without actually reading the full text of the article, which clearly says that:

On days in which the EOD animals were provided access to food, their consumption was greater than that of the AL groups; however, the data in Table I represent mean consumption averaged across all days; thus, the total dietary intake was reduced considerably by this restriction regimen. At 8 mth of age, the mean daily food intake of the EOD group was approximately 72% of that consumed by the AL group, while at 26 mth the intake of the EOD group was about 86% of that of the AL group.(3)

In other words, EOD, in this experiment, clearly did lead to de facto CR in C57BL/6 mice; once again, the relatively mild CR corresponds with a relatively mild life extension.

Again, the evidence is consistent: EOD extends lifespan to the extent that it leads to lower Calorie intake, and fails to the extent that it does not.

And, as linked above, this year we finally had a genuinely proper and direct test of the EOD hypothesis using C57BL/6 mice, involving one of the authors of (4) (Rafael de Cabo) as principal investigator. In this study, EOD-fed animals gorged on their 'feast' day, so that there was very little net reduction in food intake or body weight, just as Anson, de Cabo, and Mattson had earlier reported in (5) and used as the basis for the claim in (4) that this strain undergoes "little change in bodyweight" in response to EOD, "due to their ability to gorge when provided with food". And the result: surprise, surprise: adult-onset EOD, with very little resulting CR, lead to a small, non-statistically-significant effect on mean LS, and none at all on max.

The only real inconsistency amongst these studies is the question of why C57BL/6 mice fully compensate for their fasting days in Anson and Mattson's hands, and not in the other labs. One speculation on my part that labs in the 80s and 90s may have used food that was somewhat less energy-dense than in the later studies by Anson, Mattson, and de Cabo, making it harder to stuff down enough food to fully compensate for a day without.

Conclusion: again, EOD works to the extent that it operates as a way of imposing CR, and fails to the extent that animals compensate with extra food on their non-fasting day. If people still want to practice CR via EOD (because some find it easier to go a whole day without food than to eat regular, controlled meals) , then I think that you need to consider that this is a riskier, less consistently effective protocol, with apparently little benefit in humans and inconsistent benefits in mice; that you really ought to ease into it even more carefully than into regular CR, both because adult-onset CR generally doesn't work when imposed all at once, and because (1) clearly shows that there are risks to this EOD method in adult-onset and because it strikes me as being even more of a shock to the system than regular CR; and remember that it pretty clearly only works to the extent that it's a way f practicing an actual reduction in Calories, which you will still need to actively monitor by weighing and measuring your food, just you would by the standard protocol.


-Michael

References
1. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N.
Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age.
Mech Ageing Dev. 1990 Jul;55(1):69-87.
PMID: 2402168

2. Ingram DK, Reynolds MA (1987). The relationship of body weight to longevity within laboratory rodent species. In: Woodhead AD and Thompson KH (eds) Evolution of Longevity in Animals, pp 247Y282. Plenum Press, New York

3. Talan MI, Ingram DK.
Effect of intermittent feeding on thermoregulatory abilities of young and aged C57BL/6J mice.
Arch Gerontol Geriatr. 1985 Oct;4(3):251-9.
PMID: 4074024

4. Anson RA, Jones B, de Cabo R.
The diet restriction paradigm: a brief review of the effects of every-other-day feeding
AGE. 2005 Mar; 27(1):17-25.

5. Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP.
Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake.
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6216-20. Epub 2003 Apr 30.
PMID: 12724520 [PubMed - indexed for MEDLINE]

6. Pugh TD, Oberley TD, Weindruch R.
Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice.
Cancer Res. 1999 Apr 1;59(7):1642-8.
PMID: 10197641 [PubMed - indexed for MEDLINE]

7. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R.
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metab. 2008 Aug;8(2):157-68.
PMID: 18599363 [PubMed - as supplied by publisher]

Edited by Michael, 18 December 2011 - 02:00 PM.

[JLL]

The results from (5) still look pretty good to me. Especially the lowered insulin levels. Unfortunately they didn't measure lifespan.

Yes, there was a slight decrease in bodyweight in the IF mice, but the IF mice were much healthier than the PF mice (who were fed the same amount of energy as the IF mice chose to ate, but without fasting periods). To me it seems that combining a slight reduction in calorie intake with periodic fasting is better than just the slight reduction in calorie intake, at least in mice.

I do agree that given the choice between CR and IF (without CR), CR is the better choice in terms of increasing lifespan in rodents and probably in humans too. However, whether CR by itself is better than IF + CR is questionable. I think 10% CR + IF is much easier than 20% CR, so if periodic fasting does increase the benefits of CR, I'd choose the former.

What worries me with CR are the studies that suggest CR doesn't work in lean rodents. If that's true, then for a naturally thin person like me, reducing caloric intake significantly is both difficult and possibly worthless, so I'm basically left with different versions of IF. If it results in a slight reduction of calorie intake, that's fine by me.

Edited by JLL, 15 February 2009 - 10:13 PM.

[Matt]

What worries me with CR are the studies that suggest CR doesn't work in lean rodents. If that's true, then for a naturally thin person like me, reducing caloric intake significantly is both difficult and possibly worthless, so I'm basically left with different versions of IF. If it results in a slight reduction of calorie intake, that's fine by me.

see
http://www.imminst.o...o...st&p=295266

[VictorBjoerk]

But alternate day fasting is good for the cardiovascular system, cures autoimmune disease, improves memory,gives you more energy etc.. So it may be a very good lifestyle if you don't want to do CR.

[senseix]

Right now i fast twice a week for a total of 40 to 48 hours per week. Been doing this for a month now and i like it. When i get switched over to a more raw diet, shooting for 55% raw at first, then maybe as far as 75% over time. After that switch i might just do a 24 hour fast once per week, but until then and until i feel how my body reacts to all those changes, i'm going to stick with the 2 day fast.

[Matt]

Thank you Michael for that review. I don't understand why anyone would want to go on an alternate day fasting thing, it just doesn't seem even neccessary.

I find CR incredibly easy, and I mean I'm pretty strict on my CR, 99.98% of the time (right now consuming just 1650k/cal). I'm eating excellent and weighing and counting the calories. I can't describe how I feel when I have the money and able to buy all the ingredients and CR foods I wish. Now i have a bit more money CR is even more fun because I can experiment with foods and stuff. I jump out of bed in the morning so happy, I enjoy my food SOOO much I'm like a kid eating sweets, only I might be having a green smoothie or something, or a salad or whatever. People often wonder if I miss the old food i ate, and tease me by showing me some junk they're eating. But I'm not interested. I enjoy the food I eat now far more than I ever enjoyed any food in the past. CR is so easy, so simple, and I love the food. It's not a miserable life under CR as many people claim in the media.

Edited by Matt, 17 February 2009 - 10:19 PM.

[JLL]

I've tried CR by eating 1,750 kcal and found it rather difficult, and yet counting down from a 2,000 kcal / day diet, that's only a 12.5% CR. If you look at the rodent studies, that kind of CR will only get you a few more years, not even a decade. That doesn't seem like a trade I want to make.

Plus, I'm already very skinny, so reducing calories further would not make me look very good. Yes, I've seen your pictures, and you don't look too skinny in my opinion, but for me, cutting down from a BMI of 18 and BF 7% just doesn't seem like a good idea. I know what I look like when my BMI gets down to 17; it's that cancer-patient look. If your starting energy intake is 3,000 kcal then sure, a 25% CR is feasible and recommendable, but in very lean people it's a different story. Are they already CR'd or are they skinny otherwise?

Intermittent fasting is appealing because you get to eat as much as you like without having to count calories, which is one big hassle if you ask me.

Comparing to an average person of my height (182 cm) I probably consume less calories anyway, since I've almost always had a BMI of <20. Whether or not that counts as true CR, I don't know.

[Krell]

I am looking for antiaging techniques that maximize benefits (longevity and health) and minimize pain (feeling hungry, weak and cold).

Other than the usual supplements and EOD moderate exercise, I am fasting OAW: once a week, water only, 24 hours from 7pm to 7pm).

I take 250mg olbetam (Acipimox) at about 11am during the fast to lower blood lipids an enhance the fast effects on my body.

My scientific rationale is as follows

Studies of monthly fasting by Mormons
http://www.ncbi.nlm....pubmed/18805103

Rat studies of EOD and OAW weekly fasting, with and without Acipmox to lower blood lipids and enhance autophagy
http://www.ncbi.nlm....pubmed/15236765

C. elegans study that suggests EOD fasting less beneficial than every 2 days
http://ouroboros.wor...y-to-longevity/

OAW fasting is pretty easy and it appears to allow me to eat AL on other days without penalty.

After a year of OAW fasting, my yearly blood work has not shown any marked change,
but it has always been pretty good.

[zoolander]

I don't understand why anyone would want to go on an alternate day fasting thing, it just doesn't seem even neccessary.

Surely you have seen the published data demonstrating the benefits of IF Matt.

[randyf]

Michael Wrote:

And, as linked above, this year we finally had a genuinely proper and direct test of the EOD hypothesis using C57BL/6 mice, involving one of the authors of (4) (Rafael de Cabo) as principal investigator. In this study, EOD-fed animals gorged on their 'feast' day, so that there was very little net reduction in food intake or body weight, just as Anson, de Cabo, and Mattson had earlier reported in (5) and used as the basis for the claim in (4) that this strain undergoes "little change in bodyweight" in response to EOD, "due to their ability to gorge when provided with food". And the result: surprise, surprise: adult-onset EOD, with very little resulting CR, lead to a small, non-statistically-significant effect on mean LS, and none at all on max.

Reply:
Thanks Michael for this update on this topic.

From my read of this most recent paper it appears that max life span was increased for the EODLR group compared to the SD group.
I know you've gone over this carefully and would appreciate helping me to clarify.

From the paper:

//********************************************************************************
********

Figure 4. Effects of Resveratrol Treatment on Longevity

(E) Maximum life span was calculated as the mean of the final 20% of mice in
each group as determined by Kaplan-Meier Analysis. Compared to the SD
control group, the maximum life span was significantly increased in the
EODLR (p = 0.03) and significantly decreased in the HC control (p = 0.003)
groups. In addition, HCLR had significantly increased maximum life span
compared to the HC control group (p = 0.04), and there was a trend toward
increased life span in HCR mice compared to HC controls. *, p < 0.05 versus
SD control; #, p < 0.05 versus HC control. Error bars indicate SEM.
(F) Kaplan-Meier Survival Analyses were performed on the SD and SDHR groups,
and the curves were not significantly different. The earlier SD survival
curve (broken line) is shown for reference; n = 48 (SD, SDHR), and 60
(previous SD control) at the beginning of the experiment.

//********************************************************************************
**********

Regards
Randy F

[JLL]

I think Michael mentioned in another thread that EOD IF + Resveratrol did result in increased lifespan in mice; from what I gather, his argument is that EOD IF by itself does not result in increased maximum lifespan.

C. elegans study that suggests EOD fasting less beneficial than every 2 days
http://ouroboros.wor...y-to-longevity/

Does anyone know if this has been tested in mice or other animals? I wouldn't change from the 24/24 hour cycle to every 2 days IF based on results from C. elegans alone, because the results don't always seem to translate to rodents, let alone humans.

[randyf]

I think Michael mentioned in another thread that EOD IF + Resveratrol did result in increased lifespan in mice; from what I gather, his argument is that EOD IF by itself does not result in increased maximum lifespan.

Thanks JLL, but Michael quite clearly says that none of the EOD showed an increase in "max life span". Lots of interventions can increase mean life span (wearing seat belts, exercise, ect,ect), but only a few have an effect on "max life span" with CR the most wide spread across the animal spectrum.

Regards
Randy

[JLL]

This is what he posted in the other thread:

The modest increase in lifespan observed in the EOD + resveratrol group is interesting, and I'd like to see it further investigated, but even that result is somewhat weakened by the fact that the controls did not reach the historical benchmark for lifespan in laboratory mice (and this strain in particular), which is ~900 d mean and ~1200 d max (10th-decile survivorship) (see again my (2-5) below for examples); this might suggest that the benefit allowed them to compensate for suboptimal husbandry conditions, but would not actually benefit animals that were better-cared-for in the first place.

[randyf]

This is what he posted in another thread:

The modest increase in lifespan observed in the EOD + resveratrol group is interesting, and I'd like to see it further investigated, but even that result is somewhat weakened by the fact that the controls did not reach the historical benchmark for lifespan in laboratory mice (and this strain in particular), which is ~900 d mean and ~1200 d max (10th-decile survivorship) (see again my (2-5) below for examples); this might suggest that the benefit allowed them to compensate for suboptimal husbandry conditions, but would not actually benefit animals that were better-cared-for in the first place.

I think he was refering to mean life span. Many folks don't seem to differentiate between mean life span and max life when evaluating EOD
Here's what he said:

And, as linked above, this year we finally had a genuinely proper and direct test of the EOD hypothesis using C57BL/6 mice, involving one of the authors of (4) (Rafael de Cabo) as principal investigator. In this study, EOD-fed animals gorged on their 'feast' day, so that there was very little net reduction in food intake or body weight, just as Anson, de Cabo, and Mattson had earlier reported in (5) and used as the basis for the claim in (4) that this strain undergoes "little change in bodyweight" in response to EOD, "due to their ability to gorge when provided with food". And the result: surprise, surprise: adult-onset EOD, with very little resulting CR, lead to a small, non-statistically-significant effect on mean LS, and none at all on max.

Lots of folks seem to believe that EOD can increase MAX life span, but from a closer read of the data this does not appeared to be the case. MR has provided most of the leg work supporting this view (that EOD does NOT increase MAX life span other than thru plain jane CR ). Its seems that the authors of this recent paper seem to think it does (in one of the EOD groups). Since I don't have the graphs and numbers its hard to tell. I'm hoping MR will weight in on this. I might be over looking something obvious in which case I'll feel real stupid for at least 15 minutes.

Randy

Edited by chrono, 11 October 2010 - 09:02 PM.
fixed quote tag

[randyf]

This is what he posted in the other thread:

The modest increase in lifespan observed in the EOD + resveratrol group is interesting, and I'd like to see it further investigated, but even that result is somewhat weakened by the fact that the controls did not reach the historical benchmark for lifespan in laboratory mice (and this strain in particular), which is ~900 d mean and ~1200 d max (10th-decile survivorship) (see again my (2-5) below for examples); this might suggest that the benefit allowed them to compensate for suboptimal husbandry conditions, but would not actually benefit animals that were better-cared-for in the first place.

OK, I think he saying that this group, even though max life span was increased relative to the SD controls, life span did not reach what would be expected from well cared for animals in the control control group. In that case point taken. I just wish we had clean result one way or the other so this question (is there anything to EOD other than CR as regards slowing down intrensic aging) could be put to a final resting place.

I'm going to try to get the full paper with graphs to get a better feel of what the numbers are.

Thanks
Randy

[Forever21]

Thank you Michael for that review. I don't understand why anyone would want to go on an alternate day fasting thing, it just doesn't seem even neccessary.

I find CR incredibly easy, and I mean I'm pretty strict on my CR, 99.98% of the time (right now consuming just 1650k/cal). I'm eating excellent and weighing and counting the calories. I can't describe how I feel when I have the money and able to buy all the ingredients and CR foods I wish. Now i have a bit more money CR is even more fun because I can experiment with foods and stuff. I jump out of bed in the morning so happy, I enjoy my food SOOO much I'm like a kid eating sweets, only I might be having a green smoothie or something, or a salad or whatever. People often wonder if I miss the old food i ate, and tease me by showing me some junk they're eating. But I'm not interested. I enjoy the food I eat now far more than I ever enjoyed any food in the past. CR is so easy, so simple, and I love the food. It's not a miserable life under CR as many people claim in the media.

Matt,

Could you please post what you eat throughout the day?

Thanks

[JLL]

Food for thought:

Intermittent Fasting Improves Insulin Sensitivity Even without Weight Loss

After two weeks of intermittent fasting, body weight, body fat percentage and muscle energy stores were unchanged in a group of eight healthy men. Insulin levels were unchanged, but insulin activity increased.

The fact that the participants lost no weight means that the improvement in insulin sensitivity is not due to a restriction in calories but the fasting periods themselves. This lends support to the idea that periodical fasting is beneficial for insulin sensitivity.

Intermittent Fasting Reduces Mitochondrial Damage and Lymphoma Incidence in Aged Mice

Intermittent fasting without a reduction in body weight or total energy intake completely inhibited the development of a specific cancer (lymphoma) in female mice considered to be a model of accelerated aging. After four months, a third of the mice in control group had died, while all of the alternate-day fed mice were still alive and healthy.

This inhibitive effect was associated with lower reactive oxygen species (ROS) production and higher levels of enzymes protecting from free radical damage, including superoxide dismutase (SOD), glutathione and catalase.

[Michael]

All:

From my read of this most recent paper [Figure 4 from the resveratrol +/- EOD paper (PMID: 18599363/(7) of thread opener)], it appears that max life span was increased for the EODLR group compared to the SD group. I know you've gone over this carefully and would appreciate helping me to clarify.

JLL correctly interpreted my summary in this post:

The modest increase in lifespan observed in the EOD + resveratrol group is interesting, and I'd like to see it further investigated, but even that result is somewhat weakened by the fact that the controls did not reach the historical benchmark for lifespan in laboratory mice (and this strain in particular), which is ~900 d mean and ~1200 d max (10th-decile survivorship) (see again my (2-5) below for examples); this might suggest that the benefit allowed them to compensate for suboptimal husbandry conditions, but would not actually benefit animals that were better-cared-for in the first place.

In response to previousconfusion about that comment, I clarified further here:

To eyeball from ([(7) in the present thread]), Fig. 4 [C] and [E], mean and max LS for EOD-fed, "low"-dose resveratrol were ~132 and 147 weeks, or 924 and 1029 d. That is: these animals lived about as long, on average, as the controls of the same strain in numerous previous studies, including the adult-onset CR studies op cit -- and had a lower maximum LS. So a claim of "extended" LS is dubious.

The results from (5) still look pretty good to me. Especially the lowered insulin levels. Unfortunately they didn't measure lifespan.

Sure, but all the other studies I reviewed did -- including, again, a larger coauthored by some of the investigators in (5). The results are quite consistent: when EOD leads to CR, you get lifespan extension; when it doesn't, you don't. Whatever good EOD may bring, it isn't affecting aging, or even OVERALL health as it must ultimately manifest in life expectancy.

Yes, there was a slight decrease in bodyweight in the IF mice, but the IF mice were much healthier than the PF mice.

They certainly appeared to be, on the limited range of health parameters the investigators chose to look at, but the evidence shows that whatever the benefits of these changes might be, they don't impact lifespan, suggesting that there is little net benefit to overall health, and certainly no effect on biological aging. Lots of things are beneficial in some ways, but of no net benefit because they impose increased risk in others: early drugs for CVD, eg, lowered cholesterol, but there were no gains in total mortality because of increased risk of cancer or other things. That's the lovely thing about lifespan studies: they give you the whole picture of how an intervention impacts an animal's health.

And, again, in the human intermittent fasting studies I reviewed, even many of those parameters didn't pan out.

I do agree that given the choice between CR and IF (without CR), CR is the better choice in terms of increasing lifespan in rodents and probably in humans too. However, whether CR by itself is better than IF + CR is questionable. I think 10% CR + IF is much easier than 20% CR, so if periodic fasting does increase the benefits of CR, I'd choose the former.

Again, in studies I reviewed previously, they tried this out (or pretty darned close), and it didn't work: at the same Calorie intake, animals on CR fed once, twice, or 4 times a day had identical survivorship. That suggests to me that extending the interval between feedings from once every 24h to once every 48 isn't going to get you very far -- especially when (again) even the apparently beneficial effects of EOD in rodents mostly don't pan out in humans.

What worries me with CR are the studies that suggest CR doesn't work in lean rodents.

As Matt already noted, I rebutted this pretty clearly: CR works fine in lean rodents, when properly implemented.

If that's true [it's not -MR] then for a naturally thin person like me, reducing caloric intake significantly is both difficult and possibly worthless, so I'm basically left with different versions of IF.

But we know that IF without CR is "worthless" -- so you're definitely not 'left' with that .

CONTINUED BELOW ...

[Michael]

I am looking for antiaging techniques that maximize benefits (longevity and health) and minimize pain (feeling hungry, weak and cold).

Other than the usual supplements and EOD moderate exercise, I am fasting OAW: once a week, water only, 24 hours from 7pm to 7pm).

I take 250mg olbetam (Acipimox) at about 11am during the fast to lower blood lipids an enhance the fast effects on my body.

My scientific rationale is as follows

Studies of monthly fasting by Mormons

The study is interesting, though it's not a very good model for either EOD or even for what you're doing: the LDS practice is a once-monthly fast of 1-3 days. There are, moreover, some pretty significant confounders at work here. It's possible that this practice is a surrogate marker for adherence to other Mormon health practices: while they controlled for one (prohibition of smoking), as well as other conventional risk factors (BMI, age, gender, education, hypertension, hyperlipidemia, etc), they didn't adjust for the more Mormon-specific ones, such as nonconsumption of alcohol, tea, and coffee, adherence to the Sabbath (day of rest), or religious attendance (which enhances social cohesion).

And, it's only one study; unfortunately, I can't find any other prospective data on health outcomes in fasters, and the authors themselves don't cite any. Acutely, Ramadan fasting (meal compression) doesn't seem to affect outcomes for most relevant diseases (4-8), and as previously documented, it doesn't seem to have an overall positive impact on major disease risk factors (unlike CR). I'd be glad to see more research, particularly in different context (religious and non- , health-food-nut and non-), but I'd not put too much weight on this report alone.

Rat studies of EOD and OAW weekly fasting, with and without Acipmox to lower blood lipids and enhance autophagy

Yes, well, be on the lookout for important new details on this phenomenon coming later this year from Dr. Cuervo's lab ...

C. elegans study that suggests EOD fasting less beneficial than every 2 days

But -- again -- numerous studies in rodents or in controlled studies in humans evidently find little to no long-term benefit in mammals to fasting of any kind! As I've noted before, flies, worms, and other nonmammalian species make very poor models of mammalian aging. C. elegans' mature bodies are composed entirely of cells that don't divide, so they don't develop cancer; they don't live long enough to accumulate mitochondrial DNA deletions, or several other key forms of molecular and cellular damage that contribute to aging in mammals; they almost always die of starvation due to failure of the muscles in their pharynx; and they have the capacity to enter dauer state, which likely confounds any data on extended fasting periods. I'd ignore anything in C. elegans, especially as it relates to dietary manipulation.

CONTINUED BELOW ...

[Michael]

Food for thought:

Intermittent Fasting Improves Insulin Sensitivity Even without Weight Loss

After two weeks of intermittent fasting, body weight, body fat percentage and muscle energy stores were unchanged in a group of eight healthy men. Insulin levels were unchanged, but insulin activity increased. [based on (9)]

The fact that the participants lost no weight means that the improvement in insulin sensitivity is not due to a restriction in calories but the fasting periods themselves. This lends support to the idea that periodical fasting is beneficial for insulin sensitivity.

Since, however, the intervention had no effect on fasting insulin, and (while they didn't apparently measure fasting glucose or HbA1C (9)) other studies report no effect on basal or integrated glycemia, I'm not sure how beneficial this would be -- especially since, if you're practicing EOD, the next thing you're going to do is gorge on a massive meal. Indeed, the whole point of the study was to test the 'thrifty gene' hypothesis, looking at what they think was likely 'normal' dietary irregularity in Paleolithic times.

Intermittent Fasting Reduces Mitochondrial Damage and Lymphoma Incidence in Aged Mice

Intermittent fasting without a reduction in body weight or total energy intake completely inhibited the development of a specific cancer (lymphoma) in female mice considered to be a model of accelerated aging. After four months, a third of the mice in control group had died, while all of the alternate-day fed mice were still alive and healthy. [Based on (10)]

Ahem. Yes, the abstract (10) claims that "No remarkable difference was observed in the overall food consumption between alternate-fed (AF) and ad libitum (AL) mice"; and while the full paper says that "By the end of the experiment, comparing food intakes of the two groups, we observed that on the days they had free access to standard chow, the alternate-day mice ate nearly twofold amount than did the controls daily", they don't report what was going on earlier in the study, and I have a sneaking suspicion that they must not have been eating as much for the first few months, since there was a pretty significant weight difference between the 2 groups:

OAW fasting is pretty easy and it appears to allow me to eat AL on other days without penalty.

... or apparent benefit , as you indicate:

After a year of OAW fasting, my yearly blood work has not shown any marked change, but it has always been pretty good.

... and as is consistent with the cited human trial data.

I don't understand why anyone would want to go on an alternate day fasting thing, it just doesn't seem even neccessary.

I find CR incredibly easy, and I mean I'm pretty strict on my CR, 99.98% of the time (right now consuming just 1650k/cal).

While I'm happy for you that you find it easy, CR is difficult in various ways for a lot of people, and there are at least some people who find EOD to be easier (logistically or in terms of hunger management) than regular daily CR. Don Dowden, for instance, has been dealing with his jet-setting travel schedule for years by just not eating for a day or two, and there are others who just find it easier to make one big, honkin', Calorie- and nutrient-controlled meal once every day or two, and then go without eating for the rest of their time. But there are others who eat as much as they want of healthy food, don't control their Calories, and their weight doesn't budge, and they think they're getting the benefits of CR. They need to understand the clear conclusion of the research: it's the Calories, stupid.

, I'm already very skinny, so reducing calories further would not make me look very good. ... [F]or me, cutting down from a BMI of 18 and BF 7% just doesn't seem like a good idea. ... If your starting energy intake is 3,000 kcal then sure, a 25% CR is feasible and recommendable, but in very lean people it's a different story.

Believe me, I empathize!

Are they already CR'd or are they skinny otherwise?

Comparing to an average person of my height (182 cm) I probably consume less calories anyway, since I've almost always had a BMI of <20. Whether or not that counts as true CR, I don't know.

It doesn't :( . No one is 'naturally CRed' (cf the studies in lean vs overweight-prone strains of mice).Wherever you start from, you need to cut Calories. That's probably a big part of the reason why the epidemiology fails to find a longevity benefit to low BMI: people with low BMI aren't on CR. If you're already skinny, you just need to get skinnier.

But alternate day fasting is good for the cardiovascular system, cures autoimmune disease, improves memory,gives you more energy etc.. So it may be a very good lifestyle if you don't want to do CR.

First, as I posted previously, the best available studies don't confirm most of this in humans.

Second, even if it really did do all of that, you'll still leave the ineluctable molecular rot of biological aging untouched. You would be less likely to die early of premature heart disease etc, but the life expectancy curve for educated middle-class people who aren't doing anything obviously stupid to themselves (smoking, gross overweight, total sedentary lifestyle, etc) is already about as square as it's going to get, so the benefits would be limited. You'd still age and die like your neighbors, unless biomedical repair of aging damage arrives first ... and that's still a very big 'unless.' If you want to do something about aging, CR is -- for the moment -- the closest thing to a proven intervention we have, and most of the proffered alternatives (antioxidants, various other supplements, and EOD fasting) have been actively disproven.

You pays your money and you takes your bets. I'm working from both ends, attempting to slow the molecular and cellular entropy in my body to push my expiry date forward, and donating to the Methuselah Foundation and (to my deep gratitude and honor) working with Dr. de Grey to bring the availability of biomedical repair of that entropy forward. Each of us needs to make hir own call -- but with a clear understanding what's at stake, where we're at, and what the evidence says we can do about it.

-Michael

References

1. Nelson W, Halberg F.
Meal-timing, circadian rhythms and life span of mice.
J Nutr. 1986 Nov;116(11):2244-53.
PMID: 3794831; UI: 87085847

2. Nelson W.
Food restriction, circadian disorder and longevity of rats and mice.
J Nutr. 1988 Mar;118(3):286-9. Review.
PMID: 3280755; UI: 88171757

3. Masoro EJ, Shimokawa I, Higami Y, McMahan CA, Yu BP.
Temporal pattern of food intake not a factor in the retardation of aging processes by dietary restriction.
J Gerontol A Biol Sci Med Sci. 1995 Jan;50A(1):B48-53.
PMID: 7814779; UI: 95114284

4. Is there any effect of Ramadan fasting on stroke incidence?
Bener A, Hamad A, Fares A, Al-Sayed HM, Al-Suwaidi J.
Singapore Med J. 2006 May;47(5):404-8.
PMID: 16645691 [PubMed - indexed for MEDLIN

5. Impact of fasting in Ramadan in patients with cardiac disease.
Al Suwaidi J, Zubaid M, Al-Mahmeed WA, Al-Rashdan I, Amin H, Bener A, Hadi HR, Helmy A, Hanifah M, Al-Binali HA.
Saudi Med J. 2005 Oct;26(10):1579-83.
PMID: 16228059 [PubMed - indexed for MEDLIN

6. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study.
Salti I, Bénard E, Detournay B, Bianchi-Biscay M, Le Brigand C, Voinet C, Jabbar A; EPIDIAR study group.
Diabetes Care. 2004 Oct;27(10):2306-11.
PMID: 15451892 [PubMed - indexed for MEDLIN

7. Is there any effect of Ramadan fasting on acute coronary heart disease events?
Temizhan A, Dönderici O, Ouz D, Demirbas B.
Int J Cardiol. 1999 Jul 31;70(2):149-53.
PMID: 10454303 [PubMed - indexed for MEDLIN

8. Does hospitalization for congestive heart failure occur more frequently in Ramadan: a population-based study (1991-2001).
Al Suwaidi J, Bener A, Hajar HA, Numan MT.
Int J Cardiol. 2004 Aug;96(2):217-21.
PMID: 15262036 [PubMed - indexed for MEDLIN

9. Effect of intermittent fasting and refeeding on insulin action in healthy men.
Halberg N, Henriksen M, Söderhamn N, Stallknecht B, Ploug T, Schjerling P, Dela F.
J Appl Physiol. 2005 Dec;99(6):2128-36. Epub 2005 Jul 28.
PMID: 16051710 [PubMed - indexed for MEDLIN

10. Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting.
Descamps O, Riondel J, Ducros V, Roussel AM.
Mech Ageing Dev. 2005 Nov;126(11):1185-91.
PMID: 16126250 [PubMed - indexed for MEDLI

Edited by Michael, 30 August 2010 - 10:22 AM.
Request to insert graph

[JLL]

Hi Michael, thanks for your insighftul comments.

Ahem. Yes, the abstract (10) claims that "No remarkable difference was observed in the overall food consumption between alternate-fed (AF) and ad libitum (AL) mice"; and while the full paper says that "By the end of the experiment, comparing food intakes of the two groups, we observed that on the days they had free access to standard chow, the alternate-day mice ate nearly twofold amount than did the controls daily", they don't report what was going on earlier in the study, and I have a sneaking suspicion that they must not have been eating as much for the first few months, since there was a pretty significant weight difference between the 2 groups

Perhaps so. Still, it seems like an unprobable result (no lymphoma) from such a small restriction in calories in such a short period of time, since at the end the IF mice weighed more than the control mice.

It doesn't :( . No one is 'naturally CRed' (cf the studies in lean vs overweight-prone strains of mice).Wherever you start from, you need to cut Calories. That's probably a big part of the reason why the epidemiology fails to find a longevity benefit to low BMI: people with low BMI aren't on CR. If you're already skinny, you just need to get skinnier.

I don't understand how this works. If it's all about the calories (as you seem to say it is), then people who are obese must be eating more calories than skinny people. So if someone who is 180 cm tall and overweight has been eatin 3,000 kcal daily for most of their life drops their calories to 2,000 kcal, does that mean he's now CR'd? How do you define the beginning point for CR? Surely it doesn't make sense that if I've eaten 2,000 kcal for all my adult life, I start eating 3,000 kcal for 5 years, then go back to 2,000 kcal and call this CR?

Or do you mean that two people who both are of equal height and eat 2,500 kcal daily may in fact have different weights, and the one who weighs more just has it easier on CR (because he won't end up looking like a skeleton)?

Wouldn't you say the Okinawans are 'naturally CRed'? How does this differ from people who are just used to eating less from a young age?

[Forever21]

Wow Michael. Thanks.

If its all about the calories, would a less healthy food like pork rinds and high-Met foods be okay on a regular basis as long as the calorie intake is less than 2,000?

[JLL]

Wow Michael. Thanks.

If its all about the calories, would a less healthy food like pork rinds and high-Met foods be okay on a regular basis as long as the calorie intake is less than 2,000?

I very much doubt it. As far as I know, there have been no studies comparing different diets between CR groups. CR with unhealthy foods will probably increase lifespan, but who's to say CR with healthy foods won't increase it further? I mean, there is AGE buildup even with CR, just less. It's not like CR rodents live healthily all their life and then suddenly drop dead; they just seem to age slower.

[Michael]

Ahem. Yes, the abstract (10) claims that "No remarkable difference was observed in the overall food consumption between alternate-fed (AF) and ad libitum (AL) mice"; and while the full paper says that "By the end of the experiment, comparing food intakes of the two groups, we observed that on the days they had free access to standard chow, the alternate-day mice ate nearly twofold amount than did the controls daily", they don't report what was going on earlier in the study, and I have a sneaking suspicion that they must not have been eating as much for the first few months, since there was a pretty significant weight difference between the 2 groups

Perhaps so. Still, it seems like an unprobable result (no lymphoma) from such a small restriction in calories in such a short period of time, since at the end the IF mice weighed more than the control mice.

Well, first, it doesn't look to me like that was a small reduction in Calories -- but two additional things. First, of course, the animals didn't just develop cancer two days before they stopped the experiment . The difference in lymphoma incidence is precisely the result of what was going on during the months prior to the end of the study, when their weights were different.

Secondly, to have nearly a third of all animals having lymphoma at age 12 mo, after an prevalence of clinical disease of zero at 8 months, is evidence that something wasn't quite right in the controls from the beginning.

No one is 'naturally CRed' (cf the studies in lean vs overweight-prone strains of mice).Wherever you start from, you need to cut Calories. That's probably a big part of the reason why the epidemiology fails to find a longevity benefit to low BMI: people with low BMI aren't on CR. If you're already skinny, you just need to get skinnier.

I don't understand how this works. If it's all about the calories (as you seem to say it is), then people who are obese must be eating more calories than skinny people.

Mostly. Some skinnier people are eating tons but getting exercise, or have pre-existing illnesses or malabsorption issues, or what have you. But that isn't the most important bit:

So if someone who is 180 cm tall and overweight has been eatin 3,000 kcal daily for most of their life drops their calories to 2,000 kcal, does that mean he's now CR'd?

No:

How do you define the beginning point for CR?

While, unfortunately, as I've said before, determining exactly a given person's "% CR" as a translation of the equivalent rodent phenomenon is impossible in free-living, genetically unique humans, at a minimum, human CR should operationally be defined as restricting down from the level of intake that supports the lower of (a) your early-adult "setpoint" weight, and (if that 'setpoint' was already overweight) (b) a 'healthy' anthropometry, based on % body fat, waist-to-hip ratio, and (ideally) visceral adiposity. (Unless you've got a colony of a hundred or so identical twins that you can lock up and force to eat the same ad libitum diet and get the same amount of exercise for a decade or so ...).

Wouldn't you say the Okinawans are 'naturally CRed'? How does this differ from people who are just used to eating less from a young age?

No. The Okinawans aren't CRed, and they haven't been since the late 1960s. Detailed studies by Brad Willcox, Kakoto Suzuki, et al (1) show that the current generation of centenarians were CRed until that time, because of poverty; as government programs and (later) some economic prosperity made food more readily available, today's Okinawan centenarians ate more (just as a CRed rodent would do if given the chance), achieving more normal weights, while the younger generations grew up getting chubby. But no one was 'naturally CRed' at any point -- nor was their CR the result of any romantic nonsense of a cultural wisdom embodied in "hara hachi bu." (The fact that there are so many Okinawan centenarians, when they 'only' spent ~two thirds of their lives on CR, is all the stronger evidence for the efficacy of CR for humans).

If its all about the calories, would a less healthy food like pork rinds and high-Met foods be okay on a regular basis as long as the calorie intake is less than 2,000?

First, adult-onset CR doesn't work unless you get adequate nutrition, so there's little room for pork rinds. Second, we have more evidence, in humans, for eating a 'healthy' diet than we do that CR works in our species, so you'd be darned foolish not to eat a healthy diet before even contemplating a risky, unproven (albeit scientifically-grounded) radical strategy like CR. But, OTOH:

I very much doubt it. As far as I know, there have been no studies comparing different diets between CR groups. CR with unhealthy foods will probably increase lifespan, but who's to say CR with healthy foods won't increase it further? I mean, there is AGE buildup even with CR, just less.

There have been a few such studies, and the results depend on whaht kind of diet you're talking about. If the control diet is actively toxic (like, as you seem to suggest, loaded with AGE), then of course feeding a healthier diet, CRed or not, will let them live longer, as in the well-intentioned by ill-executed low-AGE diet CR study. But if the basic diet is basically OK, and the study is well-done, the controls will already have very 'square' lifespan curve, and CR will extend life by slowing aging, not by 'health food' effects. A few such studies have been done; the effect of a healthier diet is there, but it's minor in the face of a basically healthy rodent-chow diet, good husbandry, and the massive effect of CR itself.

It's not like CR rodents live healthily all their life and then suddenly drop dead; they just seem to age slower.

Yeah -- "just" .

-Michael
1. Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He Q, Curb JD, Suzuki M.
Abstract
Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world's longest-lived people and its potential impact on morbidity and life span.
Ann N Y Acad Sci. 2007 Oct;1114:434-55.
PMID: 17986602 [PubMed - indexed for MEDLINE]

Edited by Michael, 11 March 2009 - 07:44 PM.

[JLL]

While, unfortunately, as I've said before, determining exactly a given person's "% CR" as a translation of the equivalent rodent phenomenon is impossible in free-living, genetically unique humans, at a minimum, human CR should operationally be defined as restricting down from the level of intake that supports the lower of (a) your early-adult "setpoint" weight, and (if that 'setpoint' was already overweight) (b) a 'healthy' anthropometry, based on % body fat, waist-to-hip ratio, and (ideally) visceral adiposity. (Unless you've got a colony of a hundred or so identical twins that you can lock up and force to eat the same ad libitum diet and get the same amount of exercise for a decade or so ...).

Okay. What is this theory based on? In animals, no such estimates are needed; you just feed them less than they would normally eat and wait for good things to happen. But in humans, this idea of a "setpoint" weight seems somewhat shabby. Weight fluctuates depending on what and how much you eat, even during early adulthood.

I suspect if you used the estimates you've given above, most people doing CR are on a ~12.5% CR (cutting down from 2,000 kcal to 1,752 kcal). What does the animal data say on CR of this level? Would it give you half the benefits of 25% CR, and would 6.75% CR give half the benefits of that?

What about caloric abundance (I'm going to call it CA)? If you eat 200% of what your setpoint tells you to eat, will your lifespan be cut by 50%? CR seems independent of exercise, but what about eating more and exercising more (so that you eat as much as you spend) - is that equivalent to not exercising and eating moderately (assuming you again eat as much as you spend)? In other words, is it all about caloric restriction (meaning there's a point below which this whole thing kicks in) or calories in general (meaning that there's a clear correlation between lifespan and calorie intake)?

[Forever21]

First, adult-onset CR doesn't work unless you get adequate nutrition, so there's little room for pork rinds. Second, we have more evidence, in humans, for eating a 'healthy' diet than we do that CR works in our species, so you'd be darned foolish not to eat a healthy diet before even contemplating a risky, unproven (albeit scientifically-grounded) radical strategy like CR. But, OTOH:

Thanks Michael. Very very helpful.

In this context, what is "adult"? 18? 50?

What is the best way to get "adequate nutrition" before the transition to CR? By following Harvard Public Health Guide? Veggies & fruits only plus maybe some fish? Veganism to take care of methionine? The Zone?

[Matt]

Trying to gauage your percentage of CR is not much use. My first CR mistake was not gauging my ad lib calorie intake, however, even before I started CRON when I was 20 I had already lost weight at the age of 18 from simply eating a healthier diet and throwing out the sugar, sweets, crisps, fizzy drinks and incorporating more fruit, whole grains, some veg and nuts into my diet. Everyone in my family and even other friends and relatives noted my weight loss (though It was completely unintentional on my part), and I went to the doctor and she told me my BMI was 19. My family members actually convinced me to make an apppointment with the doctor to ask why I was so thin. So I did and she said everything is okay. I told her I eat healthy but I wasn't intending to lose weight. It's kind of vague now but my BMI must have been around 21 or something and dropped to around 19. Then I started CRON from a BMI of 19 and went down to 16.4 and now currently at 16.7. So by 'definition' of *CR* I must have reduced my calories since I was 18 years old. Even when I first started recording my first biomarkers like temperature, blood pressure, pulse, they all were within CRON ranges (bp was 100/60, pulse 60, waking temperature was 35.8 or something).

It's interesting that the majority of CRONers are reducing calorie intake from an overweight or high normal BMI of 25. Are these people doing the kind of 'anti aging' level of CR taht is used in rodent studies? I understand that Michael says its nothing at all to do with weight, but should you expect for CR to at least put you at a really LOW BMI. Are people actually reducing their calorie intake from their early adult set point, or their over-fed weight at 50 (when most people start CR).

Because of the confusion and very little use of knowing your percentage CR I just go with whatever calorie/weight level I feel somewhat comfortable with. So whatever the % of my CR is irrelevant, because even if I did know it I would be unwilling to go below a BMI of 16 anyway because for myself I don't think its a good idea. Just a gut feeling and not having the confidence in maintaining such a very low BMI. But others including Michael have mantained a BMI in the 15's for many years without problem.

Edited by Matt, 12 March 2009 - 11:07 PM.

[Matt]

is it all about caloric restriction (meaning there's a point below which this whole thing kicks in) or calories in general (meaning that there's a clear correlation between lifespan and calorie intake)?

I don't have the full the other one to this from Dean's page, and last time was not able to access it, but this will do.

Edited by Matt, 12 March 2009 - 07:29 PM.

[JLL]

Thanks. I'd like to see what happens when you overfeed the treated animals; does the linear relationship continue then? Also, the smallest CR in the graph is 25%, which is quite a lot. Hasn't anyone studied 10% CR?

[Michael]

All:

Still vaguely hoping to someday get back to various questions on this from JLL and others, but meanwhile:

Yet another study to demonstrate that EOD feeding gives exactly the lifespan extension you'd expect from the concomitant reduction in Caloric intake -- no more, no less:

Longevity characteristics of normal and GHRKO mice on mild CR
To determine whether the previously documented differential responses of GHRKO and normal (N) mice to 30% CR may have been limited to this level of dietary restriction, we conducted an additional longevity study using a milder degree of CR in both mice. ... Mice were gradually shifted to EOD by placing them on every third day fast for the first week and then EOD feeding throughout the remainder of the study. The survival of male mice used in this study (approximately 15–20 per phenotype/dietary treatment) was evaluated once all four groups reached median lifespan. At the time of analysis, the remaining survivors from this still ongoing study were 6% of the N AL, 43% of the N CR, 41% of the KO AL and 46% of the KO CR mice. Log-rank analysis for partial survivorship was conducted. At the time of analysis, all female treatment groups did not yet reach median lifespan. Animals in the longevity study were checked daily for health and survival, and were handled only for cage changes and bi-weekly body measurements. Animals that appeared near death (listless, unable to walk, and cold to the touch) or had large bleeding neoplastic growth approaching 10% of their body weight were euthanized and date of euthanasia was considered date of death...

Every other day (EOD) feeding resulted in approximately a 10–15% reduction in the average daily food intake compared to ad libitum (AL) control mice (data not shown) [21], [22]. In normal male mice, EOD feeding led to a 16% increase in median lifespan (N AL = 851 days vs. N EOD = 1010 days, hazard ratio (HR) 2.62 confidence interval (CI) 1.31–6.03). In contrast, median lifespan of GHRKO mice was not extended (KO AL = 1178 days vs. KO EOD = 1158 days, HR 1.063, CI 0.50–2.29). Compared to N AL mice, EOD feeding increased overall lifespan in normal mice as evaluated by log-rank analysis (P<0.008); however, there were no significant diet effects in GHRKO mice (P = 0.6727). Thus, a milder and different form of CR that increased longevity in normal control mice failed to further increase the lifespan of long-lived GHRKO mice, corroborating our previous findings using a more severe (30%) traditional CR regimen(1)

As noted previously, the CR GHRKO males at 30% CR in their previous study (2) displayed nominal, but statistically nonsignificant increases in average (1,145 ± 38 vs 1,171 ± 27 d) and median (1,165 vs 1,179 d) lifespan, with statistically-significant differences finally emerging in maximal LS (1,362 ± 11 vs 1,468 ± 15 d for the last 10% of survivors). It's not clear whether the researchers intend to follow this newer study (1) thru' to the end: these data were collected at median LS, and the study was mostly about insulin signaling, which required them to take liver and skeletal muscle tissue samples; it's not clear if the animals were sacrificed, or if they just took biopsies. Also, their sample size ("15–20 per phenotype/dietary treatment") was so small that a statistically significant difference even at 30% CR would be highly unlikely even in wild-type animals, let alone at such mild CR (15%, imposed via EOD).

But the data on median LS for wild-type animals (16% increase) are consistent with the %CR.

-Michael

References
1: Bonkowski MS, Dominici FP, Arum O, Rocha JS, Al Regaiey KA, Westbrook R, Spong A, Panici J, Masternak MM, Kopchick JJ, Bartke A. Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity. PLoS ONE. 2009;4(2):e4567. Epub 2009 Feb 23. PubMed PMID: 19234595

2. Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A.
Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction.
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7901-5. Epub 2006 May 8.
PMID: 16682650 [PubMed - indexed for MEDLINE]