How much of CR in rodents is a time-restricted eating effect?

[sirtuin]

I'm curious if some eating windows, macronutrient cycles, and meal frequency practices might offer health and longevity benefits beyond others.

 

One practice might include a large calorie restriction on some days, and a higher amount of calories on other days (possibly at a surplus for hormonal health), which achieves a net caloric reduction on a weekly average.  I've also heard of a "fasting mimicking diet" which reduces calories / protein / carbohydrates greatly for less than one week, achieving a net caloric reduction on a monthly average.  I've also read about "carb cycling" around activity and "protein fasting" performed once weekly.  Exercise and higher levels of non-exercise activity has been mentioned to create a caloric deficit.

 

Then, there's daily intermittent fasting.  At one extreme, there's the 22-24hr daily fast with a single large meal.  Or, a 20hr fasting and a 4 hour "eating window."  Or, 18/6 -- two meals.  16/8 -- two, three, or more meals.  Or, two meals a day, with 12 hours between meals.

 

With a focus on health / longevity biomarkers, is there an optimal way to practice CR through IF?

Edited November 12, 2015 by sirtuin

[Michael R]

In terms of the ultimate health / longevity biomarker (lifespan), and leaving aside issues of circadian rhythm, it's been shown repeatedly that the timing of Calories doesn't matter: aging is retarded and lifespan extended to exactly the same degree based on the net reduction in total intake of Calories, and the apportioning thereof doesn't matter. Notably, in studies (8-10) in which the timing of feeding has been manipulated (single day feeding vs. several smaller feeding sessions/day) while keeping Caloric intake constant, no differences in LS have been observed: the survival curves overlap, almost perfectly (8-10):
 
(Note: if the images below don't come through directly for you, it may be because your browser is blocking insecure content: try changing the "https" in your location bar to "http" (and hit return ;) ). Remember to revert back to a secure connection when you're done or you likely won't be able to post, etc).
 

 

AL vs 25% CR, apportioned as: "1) a single meal beginning at the onset of darkness (meal-fed in darkness, MFD); 2) a single meal beginning at the onset of light (meal-fed in light, MFL); and 3) six smaller meals at intervals of ~2 h beginning at the onset of darkness and ending near the onset of light, a regimen intended to approximate the pattern of ad libitum feeding (pattern-fed, PF). These schedules of food restriction were implemented with an automatic feeding apparatus (18), which controlled the timing and duration of food accessibility."(10)

 

 

 

 

Group A (61 rats) ad libitum. Group B (61 rats) were restricted to 60% in a single daily meal. Group B-2 (50 rats) were restricted to 60% provided in two daily meals at 0700 h and 1500 h.(8)

 

 
This is a direct experimental refutation of the whole notion that meal timing per se either is important to the effects of CR, or improves on CR, or is a substitution for CR, and certainly refutes the increasingly-widespread notion that just concentrating the same amount of food into one meal per day or a window of a few hours will have any substantial impact on long-term health or LS. Similarly, as repeatedly documented in the past, there is no distinct lifespan effect of alternate-day fasting/intermittent fasting/every-other-day feeding/limited feeding window that doesn't boil down do Calories. 

Now, from here on in, much of my argument is going to involve rebutting interpretations (some of them by third parties, some of them by Mattson himself) of research done by the NIA's Mark Mattson on CR and intermittent feeding (IF). Mattson has done a great deal of important CR and IF research, and takes his results seriously enough to practice IF himself; he's a distinguished researcher and fellow-traveller, and we owe him and I give him a great deal of respect. Despite this clear evidence, the suggestion -- based on the metabolic effects observed in some new studies by Mark Mattson et al (1,2) -- that various forms of IF might still slow aging and extend LS even in the absence of overall CR (ie, in the presence of compensatory overeating on the feeding day). I'd like to bring the subject in again, advance my reasons for rejecting this conclusion, & esp for thinking that IF is not a promising life-extension strategy, especially for implementation in adult animals.

The question is important. CR is, at present, the only intervention available which is proven to retard aging in mammals -- and a large body of evidence strongly suggests that it does so in humans as well. CR might make the difference between your catching the first wave of anti-aging biomedical interventions and missing them by a few months or years; it might also be crucial for your ability to actually use those interventions, as it will not just keep you alive, but biologically young. Biological youth might well be key to either implementing those technologies (especially if they merely slow down, as opposed to arrest or reverse, the aging process) or to your ability to survive them without complications (if they are invasive, physically ardurous, or prone to side-effects). Based on the evidence reviewed below, this means you'll have to adapt to a lifestyle of tracking and reducing your Calories; simply adapting an IF or "food window" strategy is unlikely to work.

Let me first point out the obvious, tho' it seems to be often overlooked in discussions on the subject. Contrary to the impression many people seem to've gotten from pop press acounts, Mattson's studies (1,2) do not provide any lifespan data. All they have shown is that IF animals undergo a variety of favorable-looking metabolic shifts, such as lower insulin and glucose levels. These shifts, while consistent with the effects of "regular" CR (limited daily feeding (LDF)), do not themselves constitute evidence that IF will lead to life extension in the absence of actual Calorie restriction.

Many studies in which IF has been implemented in juvenile animals have demonstrated LS extension (3-7) (most of them coauthored by Ingram (a coauthor of (9)) -- but in all of these studies, IF animals have undergone decreases in the ballpark of ~30% in body weight in response to IF feeding, which suggests that their overall Caloric intake has indeed been reduced -- an inference which (when measured) has been confirmed. (NB that (1), unlike (2), reported just this change).

Of these studies, (5) is of special interest. In this study,
 

Quote

Beginning at either 1.5, 6 or 10 months of age, male mice from the A/J and C57BL/6J strains and their F1 hybrid, B6AF1/J were fed a diet (4.2 kcal/g) either ad libitum every day or in a restricted fashion by ad libitum feeding every other day.

Relative to estimates for ad libitum controls, the body weights of the intermittently-fed restricted C57BL/6J and hybrid mice were reduced and mean and maximum life span were incremented when the every-other-day regimen was initiated at 1.5 or 6 months of age. When every-other-day feeding was introduced at 10 months of age, again both these genotypes lost body weight relative to controls; however, mean life span was not significantly affected although maximum life span was increased.

Among A/J mice, intermittent feeding did not reduce body weight relative to ad libitum controls when introduced at 1.5 or 10 months of age; however, this treatment did increase mean and maximum life span when begun at 1.5 months, while it decreased mean and maximum life span when begun at 10 months.

 
 

 

The dashed line is the controls; the solid line is the EOD group.

 
That is: the one strain that did not undergo a reduction in BW (& thus, by implication, a reduction in overall Caloric intake) in response to IF was the same one in which this regimen -- when implemented in adulthood -- not only failed to increase mean & max LS, but actually shortened them.

At the same time, the strains in which IF did reduce BW (& thus, by implication overall Caloric intake) DID extend LS -- but not robustly. Indeed, the lack of an increase in mean LS observed in these strains when implemented in adulthood, despite the imputed reduction in Caloric intake, is the result of the early mortality visible right around the "knee" in the survival curve (otherwise the max LS increase would, by simple arithmetic, increase av'g LS), again suggesting that this is not a promising strategy.
 
For what may be a similar case, see my analysis of Longo's recent "Fasting-Mimetic Diet" study.

Also of note is that one of these 'successful' strains was, in fact, the very same strain (C57BL/6) which (2) reported not to show reduced BW. It seems reasonable to assume that the statistically nonsignificant reduction in BW observed in (2) is simply the result of the brevity of the experiment to date, and that -- extended over a lifespan -- the small Caloric deficit slowly manifests itself, leading to the loss of BW observed in (5). Thus, even (2)'s results may actually be the result of CR.

Additionally, the idea has become popular that hormesis (the adaptive response to a specific stressor (such as hunger) with an overall upregulation of nonspecific stress-resistance ("that which does not kill you makes you stronger")) plays a key role in the effects of CR/IF/LDF, and has led to further speculation that a more 'stressful' dietary pattern (such as simply concentrating the same number of Calories into a single meal or window) will simulate CR under isocaloric feeding or enhance "regular" LDF. While hormetic effects may very well be involved in some of the narrow health benefits of these regimens (including, especially, the protective effects against neurotoxins, via a preconditioning mechanism), (15) provides several lines of evidence which strongly suggest that it is not important to the anti-aging effect per se, at least in mammals:

(a) hormesis induced by a multitude of other mechanisms (exercise, cold, heat shock, irradiation) has repeatedly failed to extend max ls in mammals (tho' an ambiguity in (13), combined with other evidence, continues to intrigue me about exposure to cold -- but that other evidence implies mechanisms other than hormesis are also at work), & doesn't clearly do so even in flies, worms etc (where most of the hormesis work has been done);

(b] most of the evidence is in poikilotherms, in whom the stressors apparently lower metabolic rate; this would (per simple-minded rate-of-living mechanisms) slow aging in such organisms -- but would be unlikely to be relevant to mammalian aging;

(c] there's inconsistency in the hormesis work, per strain & gender & other factors, which make hormesis per se questionable as a causal agent in the observed effect & certainly a poor place to directly place one's bet (ie, thru' ignoring Calories in favor of IF AL, per (2-7)'s protocols; and in particular

(d) it isn't clear that hormesis extends longevity at all, except in adverse conditions where longevity is cut short by environmental hardship (addressing extrinsic rather than intrinsic mortality; curve-squaring, not slowing aging). Where the control group is longevous, hormetic interventions seem to have little or no impact on LS. (Cf Sohal's recent analysis (16) and new results (17) using SOD-transgenic flies).

How does this square with the fact that IF seems to provide some neuroprotection against a variety of hideous neurotoxins (for instance, kainate excitotoxicity in (2) & other excitotoxins in previous IF studies) even in cases where LDF does not or is less effective? Simply put, acutely injecting the brain with hideous toxins doesn't tell us much about the kinds of challenges that the human brain is likely to experience on a day-to-day basis, or as part of "normal" aging, and thus evidently don't tell us much about the impact of this regimen on the wider aging process. In any case, I suggest that the observed results are best explained as a mixture of the increased ketone body production noted in (2) and a preconditioning hormetic mechanism. As (2) notes -- but fails to emphasize -- ketogenic diets, per se, independent of CR, are widely experimentally & clinically demonstrated to have neuroprotective effects & reduce seizures ((11-14), including against kainate (eg. (11)). The mechanism is apparently NOT any direct neuroprotective effect, nor a change in excitatory signalling; it may be a simple matter of providing an alternative energy source, which could rescue neurons in excitotoxic crisis:

"[E]pileptic patients undergoing cortical resection, demonstrated abnormal expression of [blood-brain barrier] glucose transporter molecules (GLUT1) ... Diminished ion homeostasis together with increased metabolic demand of hyperactive neurons may further aggravate the neuropathological consequences of BBB loss of glucose uptake mechanisms. Since ketone bodies can provide an alternative to glucose to support brain energy requirements, it is hypothesized that one of the mechanisms of the ketogenic diet in epilepsy may relate to increased availability of beta-hydroxybutyrate, a ketone body readily transported at the BBB." (14)

Finally, even looking at the metabolic results of (1,2) seems IMO to argue against the IF paradigm (in the absence of overall energy restriction) as a fully effective alternative to CR. Because while glycemia and resistance to excitotoxins were improved, they seem to report that IF doesn't lower IGF1 -- even when actual Caloric restriction is associated therewith.

The cardiovascular study (2), in which 4 mo old rats on an IF "regimen consumed 30% less food over time and had reduced body weights compared with rats fed ad libitum" found that wehn "The levels of .. IGF-1 in plasma were assessed at 3 and 6 months after diet initiation. ... [T]here were no significant differences in plasma IGF-1 levels among the three groups [AL, IF, and 2-DG] at either time point, although IGF-1 levels in group IF were lower after 6 months on the diet (Table 1)" -- ie, there was a nominal reduction, if you want to play voodoo, but not statistically significant, at 6 mo, and no change at all at 3 mo -- hardly a robust-sounding response.

Even more surprisingly, the excitotoxin study (1), in which IF did not lead to any reduction in weight or overall food intake, actually reported that IF *increased* IGF1: "Levels of circulating IGF-1 were decreased in mice on the [LDF] diet but increased in mice on the [iF] diet".

Granted the extensive evidence that interfering with IGF1 signalling exerts anti-aging effects in a variety of species -- including several rodent models (Ames and Snell dwarves, IGF1-receptor heterozygous knockouts, etc) -- & that LDF lowers IGF1, it seems reasonable to assert (and many do) that many of the benefits of LDF may arise from reduced IGF1. If this is the case, then IF without CR would be predicted to flop. This may be one reason for the failure of IF to increase LS when implemented in adulthood in the A/J strain.

As has been pointed out to me, however, it is possible that the significant reductions in insulin observed in IF might result in sufficiently elevated IGFBPs as to reduce actual IGF1 signalling. I would call out to Mattson et al to test this parameter.

However, whatever the actual impact on IF on this particular metabolic parameter, the weight of the evidence on LS (3-10) rather overwhelmingly argue against an anti-aging effect of IF in the absence of overall CR.


References
1. Wan R, Camandola S, Mattson MP. Intermittent fasting and dietary supplementation with 2-deoxy-D-glucose improve functional and metabolic cardiovascular risk factors in rats. FASEB J. 2003 Apr 22 [epub ahead of print] PMID: 12709404 [PubMed - as supplied by publisher]

2: 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 Apr 30 [epub ahead of print] PMID: 12724520 [PubMed - as supplied by publisher]

3: Beauchene RE, Bales CW, Bragg CS, Hawkins ST, Mason RL. Effect of age of initiation of feed restriction on growth, body composition, and longevity of rats. J Gerontol. 1986 Jan;41(1):13-9. PMID: 3941250 [PubMed - indexed for MEDLINE]

4: Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Differential effects of intermittent feeding and voluntary exercise on body weight and lifespan in adult rats. J Gerontol. 1983 Jan;38(1):36-45. PMID: 6848584 [PubMed - indexed for MEDLINE]

5: 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 [PubMed - indexed for MEDLINE]

6: Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Effects of intermittent feeding upon growth, activity, and lifespan in rats allowed voluntary exercise. Exp Aging Res. 1983 Fall;9(3):203-9. PMID: 6641783 [PubMed - indexed for MEDLINE]

7: Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Effects of intermittent feeding upon growth and life span in rats. Gerontology. 1982;28(4):233-41. PMID: 7117847 [PubMed - indexed for MEDLINE]

8. 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

9. 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

10. 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

11. Noh HS, Kim YS, Lee HP, Chung KM, Kim DW, Kang SS, Cho GJ, Choi WS. The protective effect of a ketogenic diet on kainic acid-induced hippocampal cell death in the male ICR mice. Epilepsy Res. 2003 Feb;53(1-2):119-28. PMID: 12576173 [PubMed - indexed for MEDLINE]

12. Lefevre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics. 2000 Apr;105(4):E46. Review. PMID: 10742367 [PubMed - indexed for MEDLINE]

13. Stafstrom CE. Animal models of the ketogenic diet: what have we learned, what can we learn? Epilepsy Res. 1999 Dec;37(3):241-59. Review. PMID: 10584974 [PubMed - indexed for MEDLINE]

14. Janigro D. Blood-brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. Epilepsy Res. 1999 Dec;37(3):223-32. Review. PMID: 10584972 [PubMed - indexed for MEDLINE]

15. Minois N. Longevity and aging: beneficial effects of exposure to mild stress. Biogerontology. 2000;1(1):15-29. Review. PMID: 11707916 [PubMed - indexed for MEDLINE]

16. Orr WC, Sohal RS. Does overexpression of Cu,Zn-SOD extend life span in Drosophila melanogaster? Exp Gerontol. 2003 Mar;38(3):227-30. PMID: 12581785 [PubMed - indexed for MEDLINE]

17: Orr WC, Mockett RJ, Benes JJ, Sohal RS. Effects of overexpression of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster. J Biol Chem. 2003 Jul 18;278(29):26418-22. Epub 2003 May 12. PMID: 12743125 [PubMed - in process]

[sirtuin]

Excellent information, as usual.  Thank you for the detailed response.

 

So, it sounds like it ultimately boils down to calories in vs calories out averaged over some timeframe.  The optimal eating window / meal frequency / macronutrient cycling is the one that allows an individual to most comfortably lower their body mass and decrease thyroid activity / metabolic rate / overall caloric intake.

 

If I'm interpreting this correctly, then assuming health biomarkers aren't out of range, a calorie-restricted diet rich in saturated fat, fructose, and sugar from nutritious whole foods and grass-fed animals at a low BMI producing low thyroid / hormonal activity might lead to better longevity than one which promotes a higher-BMI with greater amounts of lean muscle mass and hormonal activity.  And, it might actually be healthier to eat several times and snack throughout the day, from soon after waking to just before bed, rather than to spend most of the time fasted and try to eat this as part of large meals, or after exercise, or with a large variance in carbohydrate or protein intake.  (Or, another interpretation might show that it's just as healthy to eat once a day with an 1800 calorie high-fat, high-carb, high-protein feast of a meal as it is to eat sensibly throughout the day at an equal caloric intake.)

Edited November 13, 2015 by sirtuin

[Dean Pomerleau]

Michael,

 

I too want to thank you for this thorough and very helpful post on the apparent lack of benefits for intermittent fasting independent of CR, and the possibility of detrimental effects if practiced in lieu of CR.

 

I don't plan at this point to modify my single meal per day regime, since it suits my lifestyle and I'm accustom to it. But it's good to know that this strategy is unlikely to be important for longevity benefits.

 

But at the same time, might it be the case that IF provides mortality curve squaring benefits in humans (although perhaps not rodents), via avoidance / delay of diseases of aging, like diabetes, cancer & heart disease, by keeping glucose spikes infrequent and minimizing prolonged glucose exposure?

 

Obviously all bets are off IF raises your IGF-1 above low-normal levels...

 

--Dean

[Zeta]

Michael,

 

Excellent analysis which will compel me to go through the source material carefully to see whether I come up with the same conclusions. I probably will, when it comes to the question of the aging process per se (though I'm not sure you aren't reading (2) somewhat tendentiously ... but I will review that study in the coming week -- it was influential in my decision to try non-standard CR; I may be the one reading it lopsidedly or too hopefully).

 

Meanwhile, I'll continue with my every-three day quasi-fast diet until I get more biomarkers measured. Just found a blood pressure monitor in the house here, and see that my BP has gone from 115/65 or so (on what for me is I believe fairly extreme CR) to ~135/80. Depressing, since even if the increased ketone bodies of my diet are helping my brain, the increased blood pressure is most assuredly not....

 

Obviously all bets are off IF raises your IGF-1 above low-normal levels...

 

... in the absence of increased IGFBPs.

 

Zeta

[Michael R]

After a long delay ....

 

Excellent information, as usual. Thank you for the detailed response.

 

So, it sounds like it ultimately boils down to calories in vs calories out averaged over some timeframe. The optimal eating window / meal frequency / macronutrient cycling is the one that allows an individual to most comfortably lower their body mass and decrease thyroid activity / metabolic rate / overall caloric intake.

 

If I'm interpreting this correctly, then assuming health biomarkers aren't out of range, a calorie-restricted diet rich in saturated fat, fructose, and sugar from nutritious whole foods and grass-fed animals at a low BMI producing low thyroid / hormonal activity might lead to better longevity than one which promotes a higher-BMI with greater amounts of lean muscle mass and hormonal activity. And, it might actually be healthier to eat several times and snack throughout the day, from soon after waking to just before bed, rather than to spend most of the time fasted and try to eat this as part of large meals

Yes, if you're saying "CR diet with this composition, irrespective of timing, vs. non-CR diet with the same composition and precisely-scheduled timing." Your phrasing here is a bit ambiguous, and might suggest that your second alternative might also have a different composition, whereas CR vs. AL, diet composition, and meal timing are really separate issues. And I would say that either regimen would be better if it were low in saturated fat, fructose, and sugar rather than rich in it, unless it actively worsened your bloodwork to do so.

 

Perhaps you're now thinking "but what about all of that pro-fruit talk in the other threads?" — but even a diet very high in healthy fruit (citrus and berries, notably) can't really be called "high-fructose:" as you've just noted, for instance, in your own case "fruit supplied around 39% of my calories yesterday, providing around 20.3 grams of fructose, 20 grams of glucose, 5.1 grams of sucrose," which can hardly be called a "diet rich in fructose and sugar:" your entire daily sugars intake is less than the sucrose/HFCS in 1 x 355 mL can of Coke, which is roughly the WHO recommended limit for added sugars. The same is true for Dean, even tho' he consumes some fruit that is unusually sugar-rich and IMO of little health value. I'm less sure about Greg, whose intake intuitively seems on the high side — but not realtive to SAD, and it's really just a vague disquiet with no data behing it. Just as there are problems in lumping "potatoes" in with "vegetables" in many epidemiological studies, it's problematic to lump citrus and berries in with pears and bananas.

 

And, it might actually be healthier to eat several times and snack throughout the day, from soon after waking to just before bed, rather than to spend most of the time fasted and try to eat this as part of large meals, or after exercise, or with a large variance in carbohydrate or protein intake. (Or, another interpretation might show that it's just as healthy to eat once a day with an 1800 calorie high-fat, high-carb, high-protein feast of a meal as it is to eat sensibly throughout the day at an equal caloric intake.)

I think it's imprudent to go that far unless you're fairly severely CRed, as it goes beyond micromanaging timing and spacing and into a pattern that is likely actively harmful in terms of priming the liver for hypertriglyceridemia etc. One shouldn't do something that it's reasonable to think actively unhealthy on top of CR: smoking, high SaFA intake, not exercising, and drinking sugared soda are all bad ideas even if your diet still meets the narrow definition of CR.

 

atthe same time, might it be the case that IF provides mortality curve squaring benefits in humans (although perhaps not rodents), via avoidance / delay of diseases of aging, like diabetes, cancer & heart disease, by keeping glucose spikes infrequent and minimizing prolonged glucose exposure?

 

Obviously all bets are off IF raises your IGF-1 above low-normal levels...

You are, of course, in a significant degree asking a question that hasn't been and realistically won't be answered in humans, which is why we do rodent studies ;) . However:

 

(a) of course, rodents too are subject to diabetes, cancer, & heart disease (tho' not atherosclerosis, which is a the specific form of heart disease of particular concern to humans) — and again, IF doesn't seem to impact these independent of its effect on energy intake.

 

(b) the studies in normal-weight humans are inconsistent on glucose metabolism and other cardiometabolic effects. Strikingly, (1) (by Mattson) finds that after "8-week treatment periods (with an intervening 11-week off-diet period) ... Subjects consuming 1 meal per day exhibited higher morning fasting plasma glucose levels, greater and more sustained elevations of plasma glucose concentrations, and a delayed insulin response in the oral glucose tolerance test compared with subjects consuming 3 meals per day"! "Fasting levels of insulin, leptin, ghrelin, adiponectin, resistin,[all related to glucoregulatory function] and BDNF were not significantly affected".(1) Similarly, (2) found that in "nonobese subjects (eight men and eight women; BMI, 20 to 30 kg/m(2)) ... 22 days of alternate day fasting (36 hour fast)" had the result that "Glucose response to a meal was slightly impaired in women after 3 weeks of treatment (p < 0.01), but insulin response was unchanged. However, men had no change in glucose response and a significant reduction in insulin response (p < 0.03)" — a mixed bag at best.

 

(9) reports that "Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism": "after 2 wk of IF and a standard diet (SD) in 8 lean healthy volunteers in a crossover design, ... Peripheral glucose uptake and hepatic insulin sensitivity during the clamp did not significantly differ between the IF and SD groups. Likewise, lipolysis and proteolysis were not different ... [and it] had no effect on the phosphorylation of AKT but significantly increased the phosphorylation of glycogen synthase kinase." The one favorable-looking outcome of IF without CR in normal-weight people observed in this study was that "Phosphorylation [ie, activation] of mTOR was significantly lower after IF than after the SD" — and even then, when you read the full text, you find that it "was not different between the IF and SD groups in the basal state but was significantly lower [relative to standard diet during the clamp": mTOR activation "increased significantly during both clamps" — it was just increased to a lesser degree after IF. "We found no differences in the total muscle content of AKT, GSK-3, or mTOR ."(9)

 

Less profoundly,(14) found that 3 weeks of "alternating between days of fasting (25% of normal caloric intake) and feasting (175% of normal)" on an overall isoenergetic basis resulted in a 10% reduction in fasting insulin, but no reduction in glucose (supplementary info). Longo, in (5), finds that after the third consecutive cycle of consuming a similar fasting-mimicking diet for 5 consecutive days every month and returning to a normal diet for the rest of the month, "fasting blood glucose levels were reduced by 11.3% ± 2.3% (p < 0.001; FMD) and remained 5.9% ± 2.1% lower than baseline levels". Oddly, they don't report any data on insulin in humans, even tho' they reported it in animals It's not clear whether these subjects were overweight or not: the paper says only that they were "(generally healthy adult volunteers, ... BMI: 18.5 and up)", and reports weight outcomes as % of individual baseline weight, not in kg or as ΔBMI. But there was weight loss, so that's part of the glucose reduction. More directly on your question, neither of these studies reported anything about postprandial glucoregulation.

 

The sole study to report an improvement in post-challenge glucose metabolism following isoenergetic IF in normal-weight persons was (10). Regarding this, (9) says that

 

Although Halberg et al showed an increased glucose infusion rate during the hyperinsulinemic clamp in their study, we were not able to discern differences in peripheral or hepatic insulin sensitivity despite equal diets and a crossover design. The lack of an effect on peripheral insulin sensitivity was strengthened by the data on phosphorylated AS160-thr642-a downstream target of AKT that is involved in the translocation of GLUT4 [the glucose transporter in muscle and fat cells] to the plasma membrane. Insulin-mediated phosphorylation ofAS160 was shown to be decreased in patients with type 2 diabetes and after short-term fasting, but it is uncertain whether IF selectively influences intermediary metabolism. Such selectivity might be advantageous when adapting to periods of food abundance and food shortage.(10)

Additionally, (2), which was a separate report of the same study in (1), found that "There were no significant effects of meal frequency on heart rate, body temperature, or most of the blood variables measured. However, when consuming 1 meal/d, subjects had a significant increase in hunger ...[and] significant increases in blood pressure and in total, LDL-, and HDL-cholesterol concentrations" despite "reductions in fat mass". There was also "a significant decrease in concentrations of cortisol" — this last maybe considered desirable by some, but opposite to what happens in CR (at least during the diurnal peak). They reasonably conclude that "The present findings suggest that, without a reduction in calorie intake, a reduced-meal-frequency diet does not afford major health benefits in humans. ... A long-term reduced-meal-frequency diet that also includes a 20–30% reduction in calorie intake would more closely resemble the intermittent fasting regimen that is widely used in rodent studies."

 

And re: the lack of effect of isocaloric intermittent feeding on BDNF in normal-weight persons in (1), "many reported feeling irritable on their fasting days" in (4), which seems potentially to suggest a similar lack of happy-making BDNF. So far, limited data are inconsistent for LDF in humans: in schizophrenic patients put on a therapeutic hypocaloric diet (an imperfect model of CR in persons without psychiatric disorders, to be sure) did elevate plasma BDNF (11), whereas in elderly normal humans it did not (12).

 

Now, there is some evidence that IF, in the form of concentrating meals to align with circadian rhythms can improve cardiometabolic metabolism independent of energy intake in the context of diabetic obesity in rodents ((6,7,13); we got some subsequent followup data from Panda prior to publication at the Eighth CR Society conference, which should once again encourage people to attend the Ninth!). Even on that front, there are studies like (8) and others that I can't seem to find in my bookmarks at the moment that flatly contradict (6)'s findings, tho' I've never done the dig required to come up with a plausible explanation for the discrepancy (except, conceivably, in the specific case of (8), an interspecies difference — see below). Some human studies have reported qualitatively similar effects, but not nearly so profound in magnitude. But I presume that's NOT what you meant IAC.

 

Similarly, some human studies find that IF is a more effective weight loss strategy when accompanied by a net reduction in energy intake in overweight and obese persons; again, however, I take it that's not what you're talking about.

 

It also bears mention that IF without CR has been reported to be actively harmful in some studies (as, indeed, the evidence suggests it may be in humans to some degree (1-3)). In (15),

 

Four-month-old male Sprague-Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months ... [A]t the end of the study ... The 6-month-long ADF diet resulted in a 9% reduction (P < .01) of cardiomyocyte diameter and 3-fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the ratio of early (E) and late atrial (A) waves, in Doppler-measured mitral flow was reduced (P < .01). Pressure-volume loop analyses revealed a "stiff" heart during diastole in ADF rats, whereas combined dobutamine and volume loading showed a significant reduction in left ventricular diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve.

 

CONCLUSION: Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. [!] The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted.(15)

And (16) reports that "Long-term intermittent feeding, but not caloric restriction, leads to redox imbalance, insulin receptor nitration, and glucose intolerance:

 

[in] 4-week-old Sprague–Dawley rats ... short-term calorie restriction and intermittent feeding presented similar results relative to glucose tolerance. Surprisingly, long-term [8 months] intermittent feeding promoted glucose intolerance, without a loss in insulin receptor phosphorylation. Intermittent feeding substantially increased insulin receptor nitration in both intra-abdominal adipose tissue and muscle, a modification associated with receptor inactivation. ... In fact, long-term intermittent feeding resulted in largely enhanced tissue release of oxidants.(16)

I do wonder if this is a species effect: most of the rodent EOD studies are in mice, whereas (8,15,16) are all in rats.

 

In any event, I see little reason to think that intermittent feeding without concomitant CR will improve glucoregulatory metabolism or health generally in basically-healthy, normal-weight humans — and some reason to think it may cause some harm.

 

 

PS:

 

 

Obviously all bets are off IF raises your IGF-1 above low-normal levels...

... in the absence of increased IGFBPs.

 

I'd actually be relucatant to agree to your apparent conclusion that elevated IGF-1 is fine with concomitant elevated IGFBPs (and incidentally, I would IAC only say IGFBP3; IGFBP1 is a complicated kettle o' fish). I would say that we don't know enough about bioactivity to second-guess a high IGF-1 value, irrespective of IGFBP-3, and that you therefore want low-normal (or maybe slightly lower than reference range) absolute IGF-1 irrespective, monitoring the ratio to see that it is sufficient to suggest that that ostensibly low IGF-1 isn't actually more active than its absolute value might suggest.

 

References

1. Impact of reduced meal frequency without caloric restriction on glucose regulation in healthy, normal-weight middle-aged men and women.Carlson O, Martin B, Stote KS, Golden E, Maudsley S, Najjar SS, Ferrucci L, Ingram DK, Longo DL, Rumpler WV, Baer DJ, Egan J, Mattson MP.

Metabolism. 2007 Dec;56(12):1729-34.

PMID: 17998028 [PubMed - indexed for MEDLINE]

 

2. Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting.

Heilbronn LK, Civitarese AE, Bogacka I, Smith SR, Hulver M, Ravussin E.

Obes Res. 2005 Mar;13(3):574-81.

PMID: 15833943 [PubMed - indexed for MEDLINE]

 

3. A controlled trial of reduced meal frequency without caloric restriction in healthy, normal-weight, middle-aged adults.

Stote KS, Baer DJ, Spears K, Paul DR, Harris GK, Rumpler WV, Strycula P, Najjar SS, Ferrucci L, Ingram DK, Longo DL, Mattson MP.

Am J Clin Nutr. 2007 Apr;85(4):981-8.

PMID: 17413096 [PubMed - indexed for MEDLINE]

 

4. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism.

Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E.

Am J Clin Nutr. 2005 Jan;81(1):69-73.

PMID: 15640462 [PubMed - indexed for MEDLINE]

 

5: Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, Dubeau L, Yap LP, Park R, Vinciguerra M, Di Biase S, Mirzaei H, Mirisola MG, Childress P, Ji L, Groshen S, Penna F, Odetti P, Perin L, Conti PS, Ikeno Y, Kennedy BK, Cohen P, Morgan TE, Dorff TB, Longo VD. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015 Jul 7;22(1):86-99. doi: 10.1016/j.cmet.2015.05.012. Epub 2015 Jun 18. PubMed PMID: 26094889; PubMed Central PMCID: PMC4509734.

(See also Analysis and discussion of Longo's fasting-mimicking diet).

 

6: Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014 Dec 2;20(6):991-1005. doi: 10.1016/j.cmet.2014.11.001. PubMed PMID: 25470547; PubMed Central PMCID: PMC4255155.

 

7: Haraguchi A, Aoki N, Ohtsu T, Ikeda Y, Tahara Y, Shibata S. Controlling access time to a high-fat diet during the inactive period protects against obesity in mice. Chronobiol Int. 2014 Oct;31(8):935-44. doi: 10.3109/07420528.2014.931413. Epub 2014 Jul 1. PubMed PMID: 24984029.

 

8: Bake T, Morgan DG, Mercer JG. Feeding and metabolic consequences of scheduled consumption of large, binge-type meals of high fat diet in the Sprague-Dawley rat. Physiol Behav. 2014 Apr 10;128:70-9. doi: 10.1016/j.physbeh.2014.01.018. Epub 2014 Feb 8. PubMed PMID: 24518863; PubMed Central PMCID: PMC3989043.

 

9. Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism.

Soeters MR, Lammers NM, Dubbelhuis PF, Ackermans MT, Jonkers-Schuitema CF, Fliers E, Sauerwein HP, Aerts JM, Serlie MJ.

Am J Clin Nutr. 2009 Sep 23. [Epub ahead of print]

PMID: 19776143

 

10. Halberg N, Henriksen M, Söderhamn N, Stallknecht B, Ploug T, Schjerling P, Dela F.

Effect of intermittent fasting and refeeding on insulin action in healthy men.

J Appl Physiol. 2005 Dec;99(6):2128-36. Epub 2005 Jul 28.

PubMed PMID: 16051710.

 

11: Guimarães LR, Jacka FN, Gama CS, Berk M, Leitão-Azevedo CL,Belmonte de Abreu MG, Lobato MI, Andreazza AC, Ceresér KM, Kapczinski F, Belmonte-de-Abreu P.

Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet.

Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jun 10. [Epub ahead of print]

PMID: 18582525

 

12: Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1255-60. doi: 10.1073/pnas.0808587106. Epub 2009 Jan 26. PubMed PMID: 19171901; PubMed Central PMCID: PMC2633586.

 

13: Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012 Jun 6;15(6):848-60. doi: 10.1016/j.cmet.2012.04.019. Epub 2012 May 17. PubMed PMID: 22608008; PubMed Central PMCID: PMC3491655.

 

14: Wegman MP, Guo MH, Bennion DM, Shankar MN, Chrzanowski SM, Goldberg LA, Xu J, Williams TA, Lu X, Hsu SI, Anton SD, Leeuwenburgh C, Brantly ML. Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism. Rejuvenation Res. 2015 Apr;18(2):162-72. doi: 10.1089/rej.2014.1624. PubMed PMID: 25546413; PubMed Central PMCID: PMC4403246.

[Further discussed here

 

15: Ahmet I, Wan R, Mattson MP, Lakatta EG, Talan MI. Chronic alternate-day fasting results in reduced diastolic compliance and diminished systolic reserve in rats. J Card Fail. 2010 Oct;16(10):843-53. Epub 2010 Jul 1. PubMed PMID: 20932467; PubMed Central PMCID: PMC29534

 

16: Cerqueira FM, da Cunha FM, Caldeira da Silva CC, Chausse B, Romano RL, Garcia CC, Colepicolo P, Medeiros MH, Kowaltowski AJ. Long-term intermittent feeding, but not caloric restriction, leads to redox imbalance, insulin receptor nitration, and glucose intolerance. Free Radic Biol Med. 2011 Oct 1;51(7):1454-60. doi: 10.1016/j.freeradbiomed.2011.07.006. Epub 2011 Jul 21. PubMed PMID: 21816219.

Edited November 19, 2015 by Michael R
Restoring snipped responded-to material

[Cloud]

Hello, thanks for the interesting comments. I wanted to make an observation more down to earth. In the interviews released by Mattson (like here ) and Longo (in an italian journal here) seems to me that both skip lunch most of the time and generally appear to follow a calorie restricted diet as well as practice Intermittent fasting. this even if Longo in the "EAT, FAST & LIVE LONGER" documentary says, if I remember right, that CR appears not good for him because he is italian and likes to eat. 

 

[sirtuin]

I think it's imprudent to go that far unless you're fairly severely CRed, as it goes beyond micromanaging timing and spacing and into a pattern that is likely actively harmful in terms of priming the liver for hypertriglyceridemia etc. One shouldn't do something that it's reasonable to think actively unhealthy on top of CR: smoking, high SaFA intake, not exercising, and drinking sugared soda are all bad ideas even if your diet still meets the narrow definition of CR.

Just to clarify, you're saying eating once or twice a day might be actively harmful (priming the liver for hypertriglyceridemia) and that eating several times (3-5x + snacks?) might be a healthier approach for better longterm cardiovascular / metabolic health and insulin / leptin signaling?  In trying to reduce triglycerides, my thoughts have been that spending more time fasted would reduce serum levels, and I feel like eating less often makes me less hungry (as my meals are more satiating and ketones are elevated in the fasting window.)  My thoughts are that timing micronutrients / caloric intake around exercise might promote higher stores of lean muscle mass.

[Michael R]

 

I think it's imprudent to go that far unless you're fairly severely CRed, as it goes beyond micromanaging timing and spacing and into a pattern that is likely actively harmful in terms of priming the liver for hypertriglyceridemia etc.

Just to clarify, you're saying eating once or twice a day might be actively harmful (priming the liver for hypertriglyceridemia) and that eating several times (3-5x + snacks?) might be a healthier approach

 

No, I'm saying the reverse. The comment about spacing was in response to your suggestion (which I snipped in my reply but have now restored" that "it might actually be healthier to eat several times and snack throughout the day, from soon after waking to just before bed, rather than to spend most of the time fasted and try to eat this as part of large meals." To the contrary: it takes 3-5 hours for your body to work its way thru' the postprandial state, during which the various organs are still being stimulated with insulin and the liver is still producing TG in response; it's more prudent to consume meals late or following the completion of that cycle than to be continuously re-priming the liver. That could be done as one daily meal or several, with meal size varying accordingly, but continuous snacking is imo imprudent.

[sirtuin]

 

 

I think it's imprudent to go that far unless you're fairly severely CRed, as it goes beyond micromanaging timing and spacing and into a pattern that is likely actively harmful in terms of priming the liver for hypertriglyceridemia etc.

Just to clarify, you're saying eating once or twice a day might be actively harmful (priming the liver for hypertriglyceridemia) and that eating several times (3-5x + snacks?) might be a healthier approach

 

No, I'm saying the reverse. The comment about spacing was in response to your suggestion (which I snipped in my reply but have now restored" that "it might actually be healthier to eat several times and snack throughout the day, from soon after waking to just before bed, rather than to spend most of the time fasted and try to eat this as part of large meals." To the contrary: it takes 3-5 hours for your body to work its way thru' the postprandial state, during which the various organs are still being stimulated with insulin and the liver is still producing TG in response; it's more prudent to consume meals late or following the completion of that cycle than to be continuously re-priming the liver. That could be done as one daily meal or several, with meal size varying accordingly, but continuous snacking is imo imprudent.

Got it, thanks for the great information and resources to further digest!

[Sthira]

I'm taking a deep breath and hoping this question isn't answered in all that above (which I did struggle to read).

 

Q: Has the idea of combining non-CRed optimal nutrition with fasting five-days (all at once) per month been air ballooned and shot down here in this community?

 

That is, eat a non-SAD, no processed, little to no meat, fish, dairy diet while consuming fruits (mostly berries, citrus), veggies (limiting Russett potatoes) legumes, nuts, seeds, fungi (a wide variety of shrooms), olive oil, and a few targeted supplements to shore up (vegan) deficiencies, and combining this diet of "normal" (for you & me that'll be different) caloric intake with five-straight days of fasting per month?

 

Damned, that's still too wordy :-(

 

Eat healthy all month except for one five-day fast per month. Is that idea any good? That's what I've been doing for awhile now.

[Michael R]

I'm taking a deep breath and hoping this question isn't answered in all that above

It has been, in the discussion of Longo's recent "Fasting-Mimetic Diet" study, which was linked in the above.

 

You're forgiven :) .

 

Q: Has the idea of combining non-CRed optimal nutrition with fasting five-days (all at once) per month been air ballooned and shot down here in this community?

 

Eat healthy all month except for one five-day fast per month. Is that idea any good? That's what I've been doing for awhile now.

That is, as I imagine you must know (or else it's a remarkable coincidence) almost exactly what the Longo's recent "Fasting-Mimetic Diet" study tested. Whether the balloon should remain aloft depends on where you want it to float, and what you consider the appropriate ammunition to bring to Trial by Projectile.

 

If the goal is to do what CR does in rodents and we hope does in humans (retard the biological aging process), it seems pretty clear to me that it doesn't do the job, on the overwhelming basis that it doesn't extend rodent lifespan. Dean apparently now considers the translatability of rodent CR's effect on LS so suspect as to be dispensable, so that he endorses the FMD, tho' I continue  scratch my head as to why he then considers it beneficial and continues to believe that things in the ambit of the CR phenomenon is somehow important (such as looking at CR-related biomarkers in non-CR people).

 

However, it benefitted the rodents in other ways, and seems also to have benefitted humans; I chalk this down to obesity-avoidance and being better than AL feeding (even healthy AL feeding) for metabolic disease, and thus regard it as a reasonable alternative healthy lifestyle if you aren't going to do CR proper. are otherwise prone to overweight and metabolic disease, and find FMD easier than an equivalent level of avoidance of daily overeating. Zeta seems to regard this prospect with more enthusiasm than I think it merits.

 

Others are free to weigh in, and I welcome either Dean's or Zeta's correction of my characterizations above, and elaborations and elucidations of their views.

[Dean Pomerleau]

Michael wrote:

Dean apparently now considers the translatability of rodent CR's effect on LS so suspect as to be dispensable, so that he endorses the FMD, tho' I continue  scratch my head as to why he then considers it beneficial and continues to believe that things in the ambit of the CR phenomenon is somehow important (such as looking at CR-related biomarkers in non-CR people).

 

While I give more credence than you apparently do to the effects of hormesis, including the hormetic effects of intermittent fasting (and exercise), I don't recall ever endorsing the Fasting-Mimetic Diet (FMD), i.e. extended 5-day fasts every couple/few weeks, per se.

 

Moreover, yes I am skeptical of rodent CR data, but only about the degree to which the max longevity benefits of CR as exhibited by rodents will likely translate into human life extension, like the skepticism expressed by your colleague Aubrey.

 

Relatedly, I also no longer believe strongly in the "calories, calories, calories" mantra. Instead, I am exploring the possibility that a relative calorie deficiency (i.e. calories in - calories out), coupled with a healthy diet and lifestyle, puts the body into the "CR state" of increased repair/maintenence relative to growth/reproduction.

 

I suspect the biomarkers associated with this CR state, as observed in rodents, CR folks, and even people like me running a calorie deficit but not CRed per se, are an indication that a person has a better than average chance of living a relatively long and healthy life (e.g. into their 90s or perhaps hitting 100), barring a tragic accident, bad luck or bad genes.

 

By staying in this CR Zone as indicated by biomarkers, I hope to enjoy and modestly improve upon the health and longevity results demonstrated by the Seventh Day Adventist approach to diet and lifestyle. Call me an Eighth Day Adventist  .

 

With luck, this should put me in a position to take advantage of truly effective life extension interventions and technologies under development by you, Aubrey and others in the field of human health and longevity, which will hopefully become available in the coming decades.

 

Does that help clarify my perspective?

 

--Dean

[BrianMDelaney]

Hey gang,

Mark Mattson claimed, at the Longo conference, that "all" the CR studies in rodents are really time-restricted eating studies, since the CR'd rodents are fed one time every 24 hours, and eat all the food given to them quickly. I'm virtually certain that there are a couple studies showing CR via two or three meals throughout the day had health benefits, but my PubMed searches are drawing blanks.

Can anyone locate one of these studies?

Thanks,

Brian

Edited November 21, 2018 by Michael R
[This post merged from a separate thread; this thread contains some of those studies)

[AlPater]

Your [PMID 7814779 ; (8) in Michael's large post above] was interesting too, Brian, in the details:[In the full text]

"However, rats of Group B [the once-daily-fed/"time-restricted feeding-style" group] had a higher prevalence of skeletal muscle atrophy than the rats of Group A [AL] or Group B-2 [meal-fed twice daily, AM and PM] (p < .03)."

The cardiac and skeletal muscle mineralization level seemed to be better too, when the CRed rats ate breakfast, as well as lunch/supper.

[Matt]

Good to see you around here, Brian.

You should stop by the CR Facebook group some time as well! The activity has picked up a bit lately... 

[Mechanism]

Edited

Edited July 20, 2020 by Mechanism

[Dean Pomerleau]

Nice find Mechanism. I loved the graphical abstract of the paper. It shows the "Meal Fed" mice, who ate as much as the ad lib mice but had a narrower window of time during which to eat, were more diseases resistant and lived longer than the AL-fed mice. But 30% CR mice ate less food and in snarfed it down over an even narrower window of time, did even better:

Here are the survival curves for the three groups, with AL=black, meal-fed=blue, and CR=red:

--Dean

[Mechanism]

Edited

Edited July 20, 2020 by Mechanism