Posted 13 April 2004 - 05:19 PM
All:
This is a summary of some posts I've made on the CR Society < http//www.calorierestriction.org > forum on Every Other Day (EOD) AL feeding, as vs. Limited Daily Feeding (LDF -- "conventional" CR), esp as regards the suggestion -- based on the metabolic effects observed in some new studies by Mark Mattson et al (1,2) -- that EOD, even in the absence of overall CR (ie, in the presence of compensatory overeating on the feeding day) might still slow aging and extend LS. I'd like to bring the subject in again, advance my reasons for rejecting this conclusion, & esp for thinking that EOD 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 EOD 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 EOD animals undergo a variety of favorable-looking metabolic shifts, such as lower insulin and glucose levels. These shifts, while consistent with the effects of LDF, do not themselves constitute evidence that EOD will lead to life extension in the absence of actual Calorie restriction.
Many studies in which EOD has been implemented in juvenile animals have demonstrated LS extension (3-7) (most of them coauthored by Ingram (a coauthor of (2)) -- but in all of these studies, EOD animals have undergone decreases in the ballpark of ~30% in body weight in response to EOD 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,
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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.
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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 EOD 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 EOD 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 a (presumed) reduction in Caloric intake, suggests a lot of early mortality (otherwise the max LS increase would, by simple arithmetic, increase av'g LS), again suggesting that this is not a promising strategy.
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.
Second, in studies 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). This again suggests that the life-extending effects of EOD, when observed, are simply the result of reduced Caloric intake. This is a direct experimental refutation of the whole notion IMO, 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.
Third, while Mattson's group is promulgating the idea 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/EOD/LDF, so 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 these may very well be involved in some of the health benefits of these regimens (including, especially, the neuroprotective effects, via a preconditioning mechanism), (15) provides several lines of evidence which strongly suggest that it is not, 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;
© 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). 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).
Another line of evidence cited in favor of the benefits of EOD is the fact that it seems to provide some neuroprotection against a variety of hideous neurotoxins -- for instance, kainate excitotoxicity in (2) (& other excitotoxins in previous EOD studies from Mattson's lab). I don't think that injecting the brain with hideous toxins tells 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 I certainly don't think they tell us much about the impact of this regimen on the 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 EOD 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 EOD doesn't lower IGF1 -- even when actual Caloric restriction is associated therewith.
The cardiovascular study (2), 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 (1), in which EOD did not lead to any reduction in weight or overall food intake, actually reported that EOD *increased* IGF1: "Levels of circulating IGF-1 were decreased in mice on the [LDF] diet but increased in mice on the [EOD] 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 EOD without CR would be predicted to flop. This may be one reason for the failure of EOD 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 EOD 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 EOD on this particular metabolic parameter, the weight of the evidence on LS (3-10) seems to me to strongly argue against an anti-aging effect of EOD in the absence of overall CR.
-Michael
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