cron-web.org

[MR]

All:

CRON4HealtyFuture wrote:

> Here it is in black-and-white folks:
>
> IGF-1 is only bioavailable AFTER FEEDING.

> Oh yeah, the physiology. IGFBP-1 decreases in response to the postprandial
> insulinemic surge.......this "unleashes" IGF-1.
>
> But, but, but, intermittent fasting increases IGF-1.
>
> Yes, it does. This is likely a compensatory adaptation. This may
> attenuate fasting-related longevity benefits, if there are any.

Thanks for acknowledging that it's not at all clear that such bennies
exist; as I've argued in the past, existing evidence suggests that, in
adult organisms and/or in the absence of concommitant CR per se, there
aren't any:

http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0305&L=crsociety&P=R14231
http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0305&L=crsociety&P=R60780

(The same information was presented more clearly in this cleaned-up version:


http://mailman.aaas.org/mailman/private/sagemail/20030803.txt

Registration with SAGE mail is free: you jut need to give them an email
address & make up a password). Also, check out some of the *extensive*
followup discussion to the CR Society posts proper, and this SAGEMAIL
comment from Richard Miller:

http://mailman.aaas.org/mailman/private/sagemail/20030501.txt


> "Under physiological conditions, the insulin-sensitizing effect of IGF-I is
> evident only after feeding, when the bioavailability of circulating IGF-I
> is increased." - PMID: 16624605

Note: " after feeding ... the bioavailability of circulating IGF-I is
increased" is not the same as "IGF-1 [is] only bioavailable after feeding".

[MR]

[from May 8, 2003]

All:

In light of recent [2003] discussions about the recent studies on alternating an AL day with a fasting day ('EOD') as a method for practicing CR (1,5):

1. As Dean has already reminded folks, existing evidence suggests that this strategy, implemented in adults, will not work as a life extension strategy, and that spacing out one's defined-Calorie total food intake confers no advantage over more regular eating patterns:

http://tinyurl.com/nefyh
http://tinyurl.com/oakuz

2. The results of the 2 new studies (1,2) have become muddled in the discussion on the list. (1) reported that EOD lowers insulin and glucose and temperature, heart rate, and BP, while elevating adrenal hormones, relative to AL -- as one would expect. Contrary to what has been bandied about, however, it did NOT report that EOD yielded better glycemic (or other) results relative to 'continuous' CR (CCR), because (1) did not include a CCR control group.

It was (2) that reported alleged benefits of EOD over CCR -- including glycemia (but see below), and also rsistance to excitotoxic stress. First, a reminder that these are NOT morbidity or mortality results, but surrogate markers; don't confuse the 2. This study gives no information on the actual superiority of EOD relative to CR in terms of avoiding disease or preserving life (yet).

Second: what's got folks so excited about this is that these surrogate bennies were achieved without any decrease in total Caloric intake or BW. Whatever this may mean for these particular rodents under these particular experimental decisions, the result is most definitely not generalizable. MANY other studies -- including the recent Mattson paper (1), but also several papers (3-7) (most of them coauthored by Ingram (a coauthor of (2)) -- have very definitely reported decreases in the ballpark of ~30% in BW in response to EOD feeding, and parallel decreases (when measured) in Caloric intake. This includes (5)'s results in the very same strain of mouse used in (2).

And, indeed, in (5), the one strain of mouse which did NOT lose BW in response to EOD was refractory to the effects of EOD on longevity.

3. Folks are reading too much into (2)'s reports of better glycemia. thes values are for fasting state only; many seem to have confused fasting with postprandial &/or total AUC insulin & glucose levels (most explicitly in the comparison's to Dean's apparently poor postprandial disposal of a glucose load).

4. The benefits on kainate excitotoxicity are (I submit) readily explained as a mixture of the increased ketone body production noted in (2) and an 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 ((8-11), including against kainate (eg. (8)). 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." (11)

As to hormesis: I have no doubt taht hormesis plays a role in many of the defense pathways upregulated by CR, & it may even be that the additional stress of EOD vs CCR may be more hormetic. However, while CR-associated hormetic effects are IMO real & important mediators of some speciic CR bennies, hormesis is clearly not sufficient to account for the CR effect per se, since (per the evidence nicely reivewed, albeit without reacing the important conclusion, by a proponent of a key role of hormesis in aging (12)):

(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 EOD 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).

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. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. Holloszy JO, Smith EK. Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory". J Appl Physiol. 1986 Nov;61(5):1656-60. PMID: 3781978 [PubMed - indexed for MEDLINE]

[MR]

[from May 29, 2003]

All:

The arguments being advanced for Every Other Day (EOD) AL feeding, as vs. Limited Daily Feeding (LDF -- conventional CR) primarily revolves around an argument that EOD will induce a stronger hormetic effect than LDI. Intuitively, I can readily buy into a majror role for hormesis in CR effects -- despite how it may sound when replying to certain of this idea's more zealous advocates . But there is some data to suggest that this highly intuitive notion is mistaken. I've alread noted that (per the evidence nicely reivewed, albeit without reacing the important conclusion, by a proponent of an anti-aging effect of hormesis (16)):

(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 the 'rats with cold feet' experiment (20), combined with other evidence, continues to intrigue me about exposure to cold -- but that other evidence (esp (21)) clearly suggests mechanisms OTHER than hormesis), & 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 EOD 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).

But in addition to this, there is a new study which bears directly on the issue of getting 'extra' hormesis over & above LDF. The authors of (13) don't actually tease out this point, as that wasn't the direct subject of the paper & the authors in any case aren't biogerontologists & evidently aren't interested in aging or CR's impact on same. (13) compared "the biological effects during 8 weeks of (i) caloric restriction (Cal) and (ii) simultaneous administration of Cal plus 2 hr daily immobilization stress."

" Cal animals showed a significant loss in their relative liver and-thymus weight and a significant gain in their relative adrenal and testis weight as compared to the control animals. Cal animals had almost 2-fold higher levels of plasma corticosterone levels with a dramatic decrease in the total glucocorticoid receptor (GR) levels ... [relative to AL]. Interestingly, Cal animals showed higher levels of lipid peroxidation in both the liver and heart [NB, the next time someone starts feeling alarmed about high TBARS ] ... Cal animals had increased heat shock protein 70 (HSP 70) content in the testis."

With the exception of HSP induction (which is more recent, is well-established for CR, & is likely a good sign of hormeetic response (tho' I' REALLY like to see some data on HSP16, following the recent Kenyon (14) and Lithgow (15) studies). these are all classic signs of stress in rodents: combined with depleted ascorbate, they were central to the "alarm phase" of Selye. Yet,

"Surprisingly, hardly any significant differences were observed in either total body weight gain, organ weights, plasma corticosterone levels, or lipid peroxidation between Cal animals and Cal plus immobilization-stressed animals." In fact, coticosterone levels were significantly LOWER in CR+stress rodents than in pure CR, and the effect on HSP 70 was no greater (was in fact nominally LOWER) in the CR+stress group relative to the straight CR group.

It would appear, then, that, whatever their benefits might otherwise be, no additional hormesis induction can be gained from adding additional stressors (such ase are being hypothesized for EOD vs 'regular' CR) to simple Caloric reduction. Indeed, since these animals were on 'only' 30% CR, this study (13) suggests that a plateau in hormetic induction -- & hence in any hormesis-associated health bennies -- is reached quite easily.

I SWEARDA GAWD I wrote all of the above (& much of the below) before Alan drew our attention to (18), which contains additional details on Mattson's EOD studies precisely on this point:

"However, in contrast to large stress-induced increases in ACTH, corticosterone and epinephrine levels in AL rats, increases in these hormones in response to repeated immobilization stress sessions were reduced or absent in IF rats. Nevertheless, the IF rats exhibited robust hypothalamic/pituitary and sympathetic neuroendocrine responses to a different stress (swim)." I take this to be VERY significant: swim stress would actually require cortisol, to liberate blood sugar for physical activity, wherea immobilizatioin is (I assert) more akin to the kind of stress expected from eg. extended fasting: not demanding of Calories, but stressful & metabolically demanding.

A key implication off all of this is that hormesis either has only a very minor role in the CR effect, or that is more like an on/off switch than a dimmer dial. These animals were only 30% CR, yet additional stress failed to further increase corticosterone & HSP 70 -- likely mediators of hormesis. By contrast, CR continues to show a continual, dose-response effect on longevity as Caloric intake is pushed down to as low as 60-70%. If hormesis played a really significant role in CR, then ((13) seems to suggest) there would be a clear reduction in marginal return for additional reductions in Caloric intake beyond some cutoff point which is <=~30% CR -- and t'ain't so.

Now, ANOTHER argument for EOD being advanced is that it will further reduce IGF-1 exposure, which (due to the known bennies of interfering with IGF1 signalling) would be expected to yield LS bennies. This does make a great deal of sense, & BTW is not all that mysterious: IGF1 is generated in a permissive environment of slightly elevated insulin AND GH, as is seen in the 'valley' toward the end of the postabsorptive phase (2-3h after eating), & CR f course dramatically lowers insulin levels. EOD eating might, by reduding the number of postabsorptive periods, be expected to lower IGF1 levels; this, indeed, was Tyler Parr's thesis, summarized & discussed & advocated by me here:

http://tinyurl.com/ovrh3
[or seach at http://lists.calorierestriction.org/]

... only to be rejected shortly after, after a massive reorganization of my eating & supplement regimen:


http://tinyurl.com/rkc56
[or seach at http://lists.calorierestriction.org/]

In addition to the empirical demonstration that this idea just doesn't work on the ground to extend LS, 2 things need to be said. First, the theoretical: while I certainly agree that lower IGF1 levels contribute significantly to CR bennies (lower mitosis would indeed be expected to contribute to anti-cancer bennies, preservation of naive T-cells, & prevention of autoimmunity; plus there's the direct evidence of the rodent (& other) models of impaired IGF signalling), as I've already noted, it's quite clear that interfering with IGF-1 signalling does not fully replicate CR bennies or phenotype (22-24).

Second -- & more firmly shutting the door on the whole issue -- to my great surprise, the 2 new studies (25,26) do not support this highly intuitive & biochemically reasonable-sounding notion (he said, feeling the ghost of Greg Watson attempting to walk over his grave, only to find it eternally vacant ). In fact, they SEEM to report that EOD doesn't lower IGF1 AT ALL!

The cardiovascular study (26), in which 4 mo old rats on an EOD "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, EOD, 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(25), in which EOD did not lead to any reduction in weight or overall food intake, actually foudn that EOD *increased* IGF1.

I shit you not! "Levels of circulating IGF-1 were decreased in mice on the [LDF] diet but increased in mice on the [EOD] diet". (25)

Make-the-case arguments generally suck; as it turns out, these ones require bronchodilators to exert their full suction power. IMO, anyone continuing to practice EOD *without concomitant Caloric control* in hopes of gettin full -- or even EXTENDED -- CR-type bennies in the light of the above is a damned fool.

Some other loose ends:

A CRONie wrote:

> > 1) How often are CR rats/mice fed daily?

Normally, once daily.

> Even the feeding schedule is > probably not normal compared to free uncaged creatures including us.

Yes, extremely unnatural (rodents are natural grazers). 'course, so is CR .

> I did ask "the list" to inquire if anyone knew > whether this variable was adequately researched AND verified by > repeated testing & peer review. That seems a valid method to explore > whether there is relevance to this still open question, TTBOMCK. > (Dean pointed out MR made reference to ONE (?) periodization study, > but Dean still has a question related to this as do I, on a different > point, regarding repeated/independent verification/peer review.)

As you'd know if you'd followed the links I provided in the post to which you originally responded, the study Dean re-cited has been replicated independently atl least once:

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

http://tinyurl.com/o9vbr
[or seach at http://lists.calorierestriction.org/]

"CRON4healthyfuture" wrote:

> > It is *exactly* these types of "real-world" observations that make me laugh > at the previous generation of research from investigators who could not > tease out an effect of meal timing on CR and lifespan in their inquiry.

It isn't that they couldn't tease out an effect. In the case of intra-day concentration of food, it is that there ISN'T one (1-3). If you look at the graphs in the cited studies, there's nothing ambiguous about the survival curves: they overlap almost perfectly.

1: 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

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: 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) Taking into consideration rat/mice much higher requirements for > energy/food more often, higher metabolism, etc., and shorter lifespan, > how does this all extrapolate out to humans eating how often anyway???

A legit question, but IMO it's quite reasonable to extrapolate once/day eating as just that, for reasons given here:

http://tinyurl.com/rd2ee

I would be interested to see some info on relative time to starvation, postprandial endocrine cycles, etc.

A CRONie wrote:
> > One other positive (possibly) to eating less often is you don't > > waste the energy on more digestion cycles.
> > Dean [CRONie]. wrote:
> I'm not sure how much validity this concept has. See this message for
> the IMO rather ambiguous evidence:
> > http://tinyurl.com/b98k
> > Thanks for that info. I'll have to take time to read these thoroughly
> someday. But, the point I was -mainly- trying to make is that eating
> less often causes Gandhi, Warren, Mike C., and some others(?) to have > the sensation & feeling of having -more- energy & alertness. My
> "theory" would be that LESS TIME is spent eating & LESS CYCLES are > used, which -may- directly account for the increased feelings of > well-being or more energy.

But even if so, as others have pointed out, the fact that these folks feel better doesn't mean they are gaining any long-term anti-aging bennies. > > It may be as simple as the fact that your blood & body energies do NOT > have to be directed at digestion so often leaving more time available > for muscle & brain usage. Whether you use the same "almost" amount of > energy either way, eating more or less often, is not going to wash > away my overall point, IMO.

Granted how little energy is apparently invested in the process, I agree with Dean P that it almost certainly does.

Mike [CRONie] wrote: > > Add to this the fact that it is usually reccomended that dogs and cats > be fed once a day.

That is to put the horse before the cart: the reason for this recommendation is precisely the fact that giving pets AL access to food all day long increases their Caloric intake.

Dean [CRONie] wrote:

> > Ian [CRONie] wrote:

> > > > Consistently, the Goodrick paper (5) is cited as a reference that > > EOD fasting may actually decrease lifespan when begun in 'late life'

Actually, no: (5) shows that EOD may actually decrease LS when begun in early MIDLIFE. (5) reports that "Among A/J mice, intermittent feeding ... 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." As Dean had already suggested,

> As mentioned previously there *is* evidence in rodents (where we get > the primary evidence for CR from) that a fasting regime is good if you > start it early in life, but may in fact may be detrimental if started > beyond the human equivalent of age 30.

For mice, species max LS is <=1200 days; if we pick 120 as human max LS (which may OVERESTIMATE same IMO, but which is widely-accepted & makes the math awful convenient ), 10 mo = 304 days ~ 30.4 human years.

When it comes to LATE-life CR, all published studies have found that even 'regular' CR doesn't work, despite the fact that some of the CR-associated metabolic shifts do:

http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0207&L=crsociety&P=R8701
[or seach at http://lists.calorierestriction.org/]


This fact, NB, means that finding that much of the "CR-associated gene expression profile shifts" in early-onset CR also occurs in late-onset CR (9) is not an optimistic finding -- except, perhaps, as a NEGATIVE finding (ie, it's not impossible that we may discover some critical CR gene shifts by looking at which genes do NOT shift in response to late-onset CR).

HOWEVER, there are methodological flaws in all of the FAILED studies, & Spindler's group MAY, by doing it right, have refuted previous findings (see the recent LEF news story). I'm intending to clarify key issues on RESULTS with Dr. Spindler & post what he'll let me share, but at least his method does seem to've been sound, & what I HAVE heard about results sounds v. promising: at the very least, he CONSIDERABLY increased remaining MEAN LS -- which previous studies had failed to find. This is VERY good news, IMO, esp for folks pushing 60 at onset. And if Spindler really has induced a robust CR effect in his old rodents, that may tend to reverse the above argument about the diagnosis-from-exclusion approach to the "CR-associated gene expression profile shifts".

> Are there other papers that corroborate this finding?

Alas, no. I cited most of the EOD studies; few have been LS studies, & fewer have been adult-onset ones, & only this has actively compared different strains.

> > Has anybody tried to 'slowly' modify > > the spacing of meals in these mice - or is the 'cold turkey' > > approach all that has been studied?

AFAIK, cold-turkey is it, if one is talking about EXTENDING meal spacing beyond the 24h h period. Another protocol would be tricky, without a machine to provide food in the dead of night.

I think this is a very plausible explanation for the null effect in AJs: the onset of EOD CR is instantaneous, rather than gradual, potentially leading to the same failure of older animals to adapt to the regimen that Weindruch & Walford hypothesized to underlie the failure of their predecessors to demonstrate a robust CR effect in older animals.

With a gun to my head, I'd incline to suspect that a gradual induction on 'continuous' CR followed by EOD might work fine (provided, NB, that total Caloric intake is cut to an equivalent degree: I totally do not buy the idea that timing ALONE will reproduce the CR results, & what little evidence is available seems to support such a position). THe simple fact that one cannot (by its very nature) induce EOD gradually may very well be THE issue; OTOH, if it really just doesn't replicate the full spectrum of effects of CR proper (eg by failing to lower IGF1), it may just be intrinsically flawed for at least some genotypes.

OTOH, the simple failure of the AJs to actually reduce weight (& thus, presumably, Caloric intake) seems a much more probable explanation. In all reports in which EOD works on LS, the rodents which lose weight & (from all reporting studies) reduce their total Caloric intake in response to CR. Again, IMO, a person betting that an EOD AL gorge will equal CR per se, in the absence of actual CR, AT THE PRESENT STATE IN OUR KNOWLEDGE is being foolish -- ESP in light of the IGF1 issue.

> > I know nothing about the various mice strains employed in cr > > research, so, are the mice strains used in this study generally > > considered a good model for observing CR effects?

> As I recall [sez Dean P, in case folks've lost track fo the ">"s], > the C57BL/6J strain of mice used in [5] is a pretty standard, > long-lived strain, not one of those "die young from stupid things like > autoimmune disorder" strains, so as far as we can every try to > generalize from lab rodent studies to people, these are the kind of > rodents to use.

This is true of C57BL/6J -- but as I noted in the post to which Ian & Dean are replying, (5) found that this strain DID experience extended longevity (& weight loss) in response to adult-onset EOD. It was the A/Js that failed to do either.

All of these are inbred strains; indeed, MOST rodents used in CR studies are thus, to avoid the confounding issues of genetic diversity.

> > When I hear 'inbred' I think of friendly cousins > > and flipper hands - I'm guessing this doesn't apply to the mice used > > in a lab setting though.

Plenty of such animals are -- but not these ones. C57BL/6J are actually among the most longevous of rodent strains. AJs are not so fortunate, but they aren't patent fuckups like (NZB x NZW)F1 (model lupus) mice: in (5), their mean AL LS was 22 mo, which is not exactly a longevity record, but is respectable enough; and they DO seem to generally respond well to CR, at least in terms of cancer (1-8) -- but (again) don't respond, in normal LS terms, to EOD adult-onset (5)).

Indeed, I can imagine that inbreeding human centenarians with a family history of same might very well lead to a race of the supremely longevous. Not EVERYONE has to have deadly recessive nasties hidden in their genome -- & such could be screened or selected out.

I take it that most of us here on the list are not hampered with a consistently-fatal genetic disorder. But what we DON'T know is whether we (a) are Jeanne Calmets or folks just a little shy on the bell curve, and (b) whether we are genetically robust CR-responders or more refractory types like the DBA/2s.

[Dean [CRONie]]:

> I too am
> considering consolidating my three meals into two, if for not other
> reason than the streamlining you mention above. The primary things
> holding me back
> are:
> > 1) Social considerations:...

ISTM that social considerations might argue in FAVOR of such a scheme. If you're eating fewer, higher-Calorie meals, then with some care on AN issues one could more easily eat a 'normal' meal now & again.

> 2) Meal size/duration: I'm a bit concerned that to get the calories my
> body seems to require from the kinds of food I'm willing to eat, may
> require meals that are too big to eat comfortably at one sitting
> (think abdominal distention), and may take longer to eat than I (or
> the people I'm eating > with) are willing to spend.

This seems to me easily overcome, with highly energy-dense foods. A whack f sweet potato, eg, slathered in olive oil, could go a very long way toward your Caloric & nutritional needs in a relatively dense (& v. quickly eaten, if you don't actively slow yourself down) package.

> Furthermore, I'm not sure I'll be able to
> effectively digest and assimilate the calories/nutrients in such a
> large meal, perhaps leading to nutrient defiency, and/or further
> weight loss.

I am a LITTLE concerned about this myself: total nutrient absorption, alterations in total Caloric absorption, undergoing bone loss due to poor Ca absorption (if taken on an empty gut) or PTH-induced bone resorption (due to low blood Ca caused by failure to take same thru'out the day & esp at bedtime), etc. This concern is further exaggerated by thinking about the very large amounts of some specific nutrients which I take in relatively large doses as supplments.

When I'm rational about this, I think that this is all, after all, anal niggling (with the Ca/PTH thing as a possibly more serious case); but I'm not always so rational .

> So the question in my mind is not so much "is a fasting regime
> harmful", but rather "at what age (if ever) does a reasonable eating
> pattern (e.g. 14-24 hours of fasting every day) start to become
> harmful". ... I'm looking at a less frequent eating pattern (e.g. two
> meals per day instead of 3) for its potential convenience benefits,
> but don't want to pursue it if there is evidence it may be harmful
> relative to continuous CR.

>From available rodent data, daily meal timing is a non-issue. However:

> MR, am I correct in assuming that you believe a more frequent
> eating pattern is preferable for health/longevity reasons, since as I
> understand it you are continuing to eat 4 meals/snacks per day?

Mostly, I just find it more pleasant. And, I am also partly concerned re: nutrient absorption & PTH-induced bone resorption, as noted.

With a gun to my head, however, I actually incline to expect that there may be something to the spacing out of meals in humans, if for no other reason than to avoid the "priming" of triglyceride sytnhesis seen in rodents:

http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0203&L=crsociety&P=R39662
[or seach at http://lists.calorierestriction.org/]


This is one place where I can see that rodent LS data may possibly be less relevant to humans: normal rodents don't develop atherosclerosis (unlike ApoE knockout mice -- who are indeed (to confirm Micky Snir's recent, correct intuition) genetic fuckups, & in whom CR (naturally ) inhibits atherosclerosis (11)).

This suspicion is deepened by (12), recently posted by CRON4healthyfuture:

"When a high fat oral load is followed several hours later by further ingestion of nutrients, there is an early postprandial peak in plasma triacylglycerol (TG). Following oral fat at t=0, samples from patients that had subsequently ingested glucose [ at t=5 hours] exhibited significantly less staining for lipid within the mucosa and submucosa of the jejunum than was evident in patients that had consumed only water (p=0.028). ... During the metabolic study, oral glucose consumed five hours after oral fat resulted in a postprandial peak in plasma TG, chylomicron-TG, and apolipoprotein B48 concentration compared with oral water. ... After a fat load, fat is retained within the jejunal tissue and released into plasma following glucose ingestion, resulting in a peak in chylomicron-TG which has been implicated in the pathogenesis of atherosclerosis."

... and also (19), RE-posted with particular attention on postprandial insulin by CRON4healthyfuture. It found that "Compared with the change after 4 mo of the high-GI diet, both the low-GI and MUFA diets reduced 0-8-h mean plasma glucose concentrations[ yet m]ean plasma insulin was approximately 20% higher (P < 0.05) and FFAs approximately 12% lower (P < 0.05) after the low-GI diet than after the high-GI diet". The full text explicates, "At 4 mo, the plasma insulin AUC after breakfast tended to be lower than at baseline in all 3 treatment groups, but the changes did not differ significantly from the respective baseline values nor from each other. The insulin AUC after lunch was 88 [units] less than at baseline in the high-GI group and 56 [units] less than at baseline in the MUFA group. However, in the low-GI group, the insulin AUC after lunch [5h later] tended to be higher than at baseline by 19 [units], and this change was significantly different from those in the high-GI and MUFA groups."

I'm guessing that this is a result of the 'priming' of insulin suggested above. Low-GI diets lower the glucose jump in the first 2-3h, but lead to higher glucose at hour 4;this is exactly the blood-sugar balancing sought by many folks adopting low-GI or Zone diets, to control hunger & keep the brain well-fueled. But it MIGHT reasonably be expected to allow/stimulate insulin 'priming' at this point, even if fasting insulin remained low.

& indeed, as one would predict from this & the mechanistic studies in rodents above, "Mean 0–8h triacylglycerol increased significantly from baseline in the low-GI group by [10%], ... [whereas the] (3%) increase in the MUFA group ... [and] 0.14 ± 0.06-mmol/L (7%) reduction in the high-GI group ... did not differ significantly from their respective baseline values."

The lack of this response in the MUFA diet would perhaps then be because of a combination of lower GI (creatd by GIP and the slowing of gastric emptying by MUFA) and the reduction of TOTAL carb (precisely by the replacement of CHO with fat), leadign to lower total glucose in need of disposal & hence (all else being equal) lower insulin. This is consistent with the lower insulin & (fasting) TG previously reported in high-MUFA diets, as documented extensively in the Alb*tr*ss and elsewhere.

This is IMO again an endorsement of a high-MUFA diet, & I suggest that it may also argue for a high-MUFA AND low-GI diet, to reap the initial postprandial benefits of the latter while keeping total sugar & insulin lower due to the lower CHO of the former. However, it does tend to again suggest possible bennies for longer interprandial periods -- longer, in fact, than 5h, which I'd've thought to've been plenty. 3 meals/day (every 6h), or a return to my Tyler Parr twice/day pattern, do look potentially promising.

> But at what point in the meal frequency dimension do we suspect a
> fasting form of CR starting *hurting* you from a health/longevity > perspective?

I think we can say that, if anything, a solar day is LESS biologic/relative time to a human than to a rodent. So if one daily feed is OK in rodents, then one daily feed should also be OK for humans. IMO, caution (& the op cit circadian etc arguments) say to take seriously the suggestion from (5) that one should not go LONGER than 24h between feedings.

> And
> how does this point vary with age and/or abruptness of the fasting
> regime onset?

Well, not too many folks are starting CR much earlier than 30, so IMO the former is moot. Abruptness, again, is an interesting question.

Mike CRONie wrote:
>[Based on his gradual adjustment to extended meal spacing,] this stuff
>we always here about 5 hours or so is based on the body's habits not
>on any scientific rationale for needing refueling. Yes? No?

I think no. There IS a metabolic basis for 4-5h spacing, in the insulin:GH axis (17). The 2 hormones have a well-established axial relatioinship, suppressing one another's release & cellular action: this is why high GH eg is associated with impaired glucose tolerance. As the body enters the postabsorptive state 2-3 h after a meal, GH levels begin to rise, reaching a peak 4-5 h later, whereupon one is increasingly living off FFA released from muscle cells by GH, on glycogen-released gluconeogenic glucose.

This is a metabolic fact, not a habit, grounded in endocrinology. OTOH, there is no reason AFAICS why one should feel obliged to reset the roller coaster every time one gets to the top -- & while hanging out there may be stressful, some (like yourself) may find this to be mitigable by by acclimation.

CRBASIC wrote:

> My opinion: Since many older people NATURALLY
> cut down to one meal a day, it would appear to
> be apparently safe, and maybe even healthy.
> Doing it earlier in life may be more healthy yet.

The bodies of older people 'naturally' do all kinds of things that are bad for them. The phenomenon -- age-related anorexia -- is linked to a variety of things, from reduced lean mass (& hence Caloric intake), to loss of hunger singaling, to loss of taste sensitivity, & is believed by many researchers to be closely related to cachexia & sarcopenia in the aged; I wouldn't put too much stock in the notion that any age-related change is good for one & should be proactively adopted.


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