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Alternate-Day Fasting, Resveratrol, and CR


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#1 Michael

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Posted 08 July 2008 - 01:13 AM


All:

OK, folks ....

I don't have anything like the time required to troll thru' the monster resveratrol thread triggered by (0). Let me make the key points.

CR per se does indeed retard biological aging and extend lifespan in this and every strain of mouse in which it's been tested with appropriate protocols (no malnutrition, etc). Of particular importance, this has been repeatedly shown in the C57BL/6 NIA strain used in this study (0), including for adult-onset CR (eg. (2-4)). This is not a mutant mouse, but is a vigorous strain -- the one most commonly used in aging studies precisely because it enjoys the full maximum lifespan of the species and does not die early from some particular disease or genetic defect, allowing effects on aging itself to shine through most clearly.

EOD does not always result in lower Calorie intake in mice. How much animals overcompensate for being fasted every other day varies by mouse strain; this particular strain (C57BL/6 NIA -- an important point, to which I will return) was reported several years ago to completely compensate , so that there was next to zero reduction in actual Caloric intake: "We report that when C57BL6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained" (1). In this study, too, there was next to no reduction in Caloric intake in the EOD groups; this is shown in supplemental figure S5 (attached).

This, in fact, was supposed to be EOD's selling point: Mattson and Anson also showed that EOD feeding reproduces some of the health benefits of CR, including "reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress" (1), "produced decreases in the low-frequency component of DPV spectra, a marker for sympathetic tone, and the high-frequency component of HRV spectra, a marker for parasympathetic activity" (7), provided significant protection to heart tissue against induced infarction (heart attack) (8), "improves cardiovascular and neuroendocrine responses to stress) (9), and "improve functional and metabolic cardiovascular risk factors" (10). In the closest thing to a failure relative to CR they reported, Mattson's group found that while both EOD ("intermittent fasting"/IF) and CR "3xTgAD mice" (animals with knockins for beta-amyloid and tangle-forming tau (the characteristic brain lesions of Alzheimer's disease)) "exhibited higher levels of exploratory behavior, and performed better in both the goal latency and probe trials of the swim task, compared to 3xTgAD mice on the control diet, only 'chronic' CR animals "showed lower levels of Abeta1-40, Abeta1-42 and phospho-tau in the hippocampus ... IF may therefore protect neurons against adverse effects of Abeta and tau pathologies on synaptic function" but did not actually reduce the burden of aging damage itself (6).

Based in large part on this, Mattson has been arguing for years that EOD feeding might be a viable alternative to CR for human use, which might be more tolerable for some and would avoid loss of mass, which is after all a quality-of-life issue and also does carry some risks (such as the lighter bones -- although (as I discuss in a series of posts about CR, bones, and 'osteoporosis') the evidence does seem to imply that the age-related degeneration of the bones is simultaneously avoided, meaning that the bones are likely of higher quality at the ages where it counts. They bolstered their case (and brought Don Ingram aboard) by pointing to studies from the 1980s (11-13), in which rodents of this same strain showed an apparent life extension from EOD. And indeed, if you look all over the Imminst boards and (depressingly) even on the CR society list (where it's been refuted repeatedly), lots of people got the impression from all of this that EOD without a reduction in Calories could extend life just as CR itself does.

This was Mattson's hypothesis -- not something that anyone had ever demonstrated experimentally. In fact, no study has ever actually shown that EOD animals gain any extension of maximum lifespan without concomitant reduction in Calorie intake. Mattson's various studies (1, 6-10) were not lifespan studies, and the earlier studies from the 1980s (11,12) did not record the EOD animals' food intake -- and indeed, actually showed that the EOD animals' body weights were lower than those of AL-fed animals, suggesting some degree of CR. The illuminative exception was the A/J mice in (13), whose weight was not reduced by EOD feeding -- and, tellingly, those mice got no life extension benefits from the treatment. These papers were also confounded by a lot of other things, most notably the fact that the EOD animals in (11) (but not 12,13) were also doing voluntary wheel-running in their cages, and that the control animals (especially in (12)) were unusually short-lived, compromising all claims of "extended" LS.

So in addition to finally disproving the thesis that resveratrol would mimic CR's anti-aging effect (as shown by the lack of effect on lifespan), this study finally put to rest the idea that EOD feeding without concomitant reductions in Calorie intake would mimic CR's benefits.

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.

IAC, none of this applies to anyone not eating an EOD diet.

The observed health benefits in resveratrol-fed are also interesting, and again raise the question (suggested in (5) and elsewhere, and consistent with (14)) that if cancer could be taken out of the equation (a tall order!) there might well be a significant life extension benefit from this combination. Here too however we must be cautious: the antiinflammatory benefits are consistently seen in rodent studies involving antioxidants, and aren't necessarily anything special; the benefit to bones, in particular, might just be a phytoestrogenic effect. The effects on cataracts and locomotor function (as demonstrated on the rotarod) definitely merit further investigation -- but not self-experimentation.

Finally: mice and rats absorb a heck of a lot more resveratrol, as the Phase II conjugation metabolites (glucuronides, sulfates, glycones), and especially as the free molecule which clearly will change their bioactivity; as others have noted on ImmInst (based on back-of-the-envelope calculations from published studies, to which I add (15), which reported a peak plasma total resveratrol of 416 to 471 µg/L (~2 µmol/L) and a peak pure resveratrol of ~37 nM for a 25 mg/70 kg human -- equivalent to 5.9 µM and 100 nM per mg, respectively), it's likely that a human would need 2-6 times the straight-extrapolated dose, so all of this talk of "a low dose of resveratrol" in either of these studies (0,14) really makes little sense; this is all the more complicated by both the potential cellular-level cleavage of the glucuronide (16) and the stubstance's extremely rapid plasma clearance/metabolism. What the 'right' dose is to mimic the rodent effects (if it can be done at all), and the appropriate dosing regimen, are still largely guesswork, and itself sufficient to merit much greater caution than has been exercised to date by many of us.

-Michael

References
0. 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.
Abstract
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metab. 2008 Jul 2. [Epub ahead of print]
PMID: 18599363 [PubMed - as supplied by publisher]

1. 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]

2. Weindruch R, Walford RL.
Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence.
Science. 1982 Mar 12;215(4538):1415-8.
PMID: 7063854 [PubMed - indexed for MEDLINE]

3. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA.
The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice.
Free Radic Biol Med. 2004 Apr 15;36(8):1043-57.
PMID: 15059645 [PubMed - indexed for MEDLINE]

4. 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]

5. Spindler SR, Mote PL.
Screening candidate longevity therapeutics using gene-expression arrays.
Gerontology. 2007;53(5):306-21. Epub 2007 Jun 15. Review.
PMID: 17570924 [PubMed - indexed for MEDLINE]
[Lifespan curve reproduced (crudely) here; interventions initiated at 14 months -MR]

6. Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, Mattson MP.
Abstract
Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease.
Neurobiol Dis. 2007 Apr;26(1):212-20. Epub 2007 Jan 13.
PMID: 17306982 [PubMed - indexed for MEDLINE]

7. Mager DE, Wan R, Brown M, Cheng A, Wareski P, Abernethy DR, Mattson MP.
Free Full Text
Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats.
FASEB J. 2006 Apr;20(6):631-7.
PMID: 16581971 [PubMed - indexed for MEDLINE]

8. Ahmet I, Wan R, Mattson MP, Lakatta EG, Talan M.
Free Full Text
Cardioprotection by intermittent fasting in rats.
Circulation. 2005 Nov 15;112(20):3115-21. Epub 2005 Nov 7.
PMID: 16275865 [PubMed - indexed for MEDLINE]

9. Wan R, Camandola S, Mattson MP.
Free Full Text
Intermittent food deprivation improves cardiovascular and neuroendocrine responses to stress in rats.
J Nutr. 2003 Jun;133(6):1921-9.
PMID: 12771340 [PubMed - indexed for MEDLINE]

10. Wan R, Camandola S, Mattson MP.
Free Full Text
Intermittent fasting and dietary supplementation with 2-deoxy-D-glucose improve functional and metabolic cardiovascular risk factors in rats.
FASEB J. 2003 Jun;17(9):1133-4. Epub 2003 Apr 22.
PMID: 12709404 [PubMed - indexed for MEDLINE]

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

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

13. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N.
Abstract
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]

14. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA.
A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice.
PLoS ONE. 2008 Jun 4;3(6):e2264.
PMID: 18523577 [PubMed - in process]

15. Goldberg DM, Yan J, Soleas GJ.
Abstract
Absorption of three wine-related polyphenols in three different matrices by healthy subjects.
Clin Biochem. 2003 Feb;36(1):79-87.
PMID: 12554065 [PubMed - indexed for MEDLINE]

16. Wang LX, Heredia A, Song H, Zhang Z, Yu B, Davis C, Redfield R.
Abstract
Resveratrol glucuronides as the metabolites of resveratrol in humans: characterization, synthesis, and anti-HIV activity.
J Pharm Sci. 2004 Oct;93(10):2448-57.
PMID: 15349955 [PubMed - indexed for MEDLINE]

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#2 Matt

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Posted 08 July 2008 - 02:35 PM

That was very clearly explained, thank you! I just took another look at the body weights of the EOD group, they're pretty much the same as the standard diet... Never realized that what the researchers kept mentioning was Dietary Restriction was actually not CR at all, but pure EOD without a reduction in calorie intake.

Very interesting stuff :)

Matt

Edited by Matt, 08 July 2008 - 03:05 PM.

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#3 kismet

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Posted 09 July 2008 - 06:59 PM

Thank you for clearing that up Michael. Those two studies (11, 12) were bugging me for a long time. No wonder people are confused, those abstracts really are rendered useless if the reseachers say "EOD" but don't tell whether it was ad lib or in fact CR (at least mentioning the weight of their rats).

The benefits of Res and IF on quality of life are now well established it seems, but this study shows they may act in a synergetic manner. Well, if it wasn't making up for bad husbandry.
So maybe both IF and Res can retard certain aspects of aging, which taken together, makes them effective.

You said taking cancer out of the equation might help, maybe EOD did exactly that. Even though IF does not reduce IGF-1..
"Alternate fasting, that was initiated in middle age mice through a 4 month period, reduced significantly the incidence of lymphoma (0% versus 33% for controls)"

1. Descamps O et al. Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Mech Ageing Dev. 2005 Nov;126(11):1185-91.
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#4 AaronCW

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Posted 13 July 2008 - 12:25 AM

Thank you for clearing that up Michael. Those two studies (11, 12) were bugging me for a long time. No wonder people are confused, those abstracts really are rendered useless if the reseachers say "EOD" but don't tell whether it was ad lib or in fact CR (at least mentioning the weight of their rats).

The benefits of Res and IF on quality of life are now well established it seems, but this study shows they may act in a synergetic manner. Well, if it wasn't making up for bad husbandry.
So maybe both IF and Res can retard certain aspects of aging, which taken together, makes them effective.

You said taking cancer out of the equation might help, maybe EOD did exactly that. Even though IF does not reduce IGF-1..
"Alternate fasting, that was initiated in middle age mice through a 4 month period, reduced significantly the incidence of lymphoma (0% versus 33% for controls)"

1. Descamps O et al. Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Mech Ageing Dev. 2005 Nov;126(11):1185-91.


Sorry, but I've looked over this whole report and can't figure out what IF stands for.
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#5 Athanasios

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Posted 13 July 2008 - 01:03 AM

Sorry, but I've looked over this whole report and can't figure out what IF stands for.

Intermittent Fasting
AKA Alternate Day Fasting
AKA Every Other Day Fasting
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#6 Castiel

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Posted 30 January 2014 - 12:34 AM

So in addition to finally disproving the thesis that resveratrol would mimic CR's anti-aging effect (as shown by the lack of effect on lifespan),

Resveratrol has extended the lifespan of fish, obese mice, genetically induced mitochnodrially dysfunctional mice, and in senescence accelerated SAMP8 and SAMR1 mice. As for the studies on normal mice that failed, we would have to see methods, conflict of interest(after all resveratrol if it did what was hypothesized would basically demolish practically the entire pharmaceutical industry), etc

Edited by Castiel, 30 January 2014 - 12:36 AM.

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