if the control group was indeed given more 'empty calories', how could one claim so strongly that it was the sum of calories, rather than their relative 'emptiness', that was the driving force behind shorter life spans?)
First and foremost, precisely because they were empty Calories. If the Calories come with extra nutrients, then you wouldn't be able to separate out the effects of the nutrients from the effects of the Calories: the CR group would get less nutrients, AND fewer Calories.
That said, there is lots of additioinal evidence to show that it's the darned Calories. For one thing, doing the reverse experiment -- giving the animals multiples of the RDA for essential nutrients -- doesn't extend, and may shorten, their lives. (1) For another thing, there are actually plenty of studies where another form of the reverse study (ie, the CR animals are given smaller quantities of the
exact same chow as the AL ones, leading to sub-rodent-'RDA' intake), and if you start them young enough, they STILL live longer and healthier lives than the AL animals.
Moreover, there are a zillion studies where AL animals are given nutritional supplements, with no effect on lifespan (unless the animals are, themselves, short-lived, so it's not an actual EXTENSION of their lives, but a partial NORMALIZATION of miserably short ones -- eg, all the hype about resveratrol feeding to morbidly obese, diabetic, high-saturated-and-trans-fat-and-sugar-fed mice supposedly 'extending' their lives, but later being shown to have no effect on normal animals given a normal diet).
And finally, there are studies involving such short-lived mice (such as disease-prone mutants (2) and carcinogen-fed rats (3)) where the AL animals are given extra nutritional supplements that partly normalize their shortened lives, and the CR versions of the same animals still get less (2) or similar (3) rates of cancer, and in the latter case (a) the CR was incredibly mild (maybe 5-10% -- see material at reference), and (b) the benefits of the supplement were additive with CR anway. (Note, in fact, in both stueies that the supplement-fed mice weigh less than the controls, suggesting that part of the benefit may have been from crypto-CR due to eg. food inpalatability with all that junk in the food).
-Michael
1. Kokkonen GC, Barrows CH:
The effect of dietary vitamin, protein and intake levels on the life span of mice of different ages. AGE.1985 Jan;8(1): 13-17,
2: Mai V, Colbert LH, Berrigan D, Perkins SN, Pfeiffer R, Lavigne JA, Lanza E, Haines DC, Schatzkin A, Hursting SD.
Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res. 2003 Apr 15;63(8):1752-5. PubMed PMID: 12702556.
3. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK.
Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst. 2003 Nov 5;95(21):1578-86. PubMed PMID: 14600090.
The abstract of this study is unintentionally misleading, and unfortunately they never break down the results group-by-group, but it's clear from the full text that the benefits of even this mild CR (20% -- and see below) were superior to those of the tomato powder fed AL. and that they were also additive, so that eating tomato powder CR was of further benefit:At 6 weeks of age, rats were randomly assigned to one of three semi-purified AIN-93G-based experimental diets ... One diet contained control beadlets ...(n = 64 rats), the second contained lycopene beadlets (Hoffmann-La Roche) (n = 65 rats), and the third contained tomato powder ... (n = 65 rats) ...
All rats initially consumed one of the three diets, with unlimited access to food (defined as ad libitum). When they reached 10 weeks of age (3 days after carcinogen administration; see below), the rats in each dietary group were further subdivided and randomized to ad libitum or 20% total dietary restriction for the remainder of the study. Diet-restricted rats were fed daily a quantity of food equal to 80% of the average daily intake of ad libitum-fed rats, which was recalculated weekly until rats were 17 weeks of age, when food intake had stabilized. From that point on, food intake in the ad libitum-fed group was precisely measured every 4 weeks, and the amount of food provided to the diet-restricted groups was adjusted accordingly. ...
rats fed tomato powder experienced longer prostate cancer-free survival than rats in the other two dietary groups (Fig. 3, A). A Cox proportional hazards model, restricted to the control and lycopene beadlet diets (Table 4), showed that, after controlling for diet restriction, rats fed the control and lycopene beadlet diets experienced similar survival (P = .63). ... By contrast, for the model restricted to rats fed the control and tomato powder diets, rats fed the tomato powder diet experienced a statistically significantly longer survival than the rats fed the control diet (hazard ratio [ HR ] = 0.74, 95% confidence interval [CI] = 0.59 to 0.93; P = .009) after controlling for diet restriction. This result remained statistically significant even after applying the Bonferroni adjustment. Finally, the Cox model comparing survival of tomato powder- and lycopene-fed rats suggested that rats fed tomato powder had prolonged survival compared with lycopene-fed rats after controlling for diet restriction, but the difference did not reach statistical significance (P = .07). The percentages of rats dying with some form of prostate cancer (adenocarcinoma, carcinoma in situ, or sarcoma) were 80% (95% CI = 68% to 89%), 72% (95% CI = 60% to 83%), and 62% (95% CI = 48% to 75%) for the control, lycopene, and tomato powder groups, respectively. ...
The percentages of rats that died with prostate cancer were 79% (95% CI = 69% to 86%) and 65% (95% CI = 54% to 74%) for the ad libitum and diet-restricted groups, respectively. Kaplan-Meier survival functions for the two groups were statistically significantly different (log-rank test, P = .03), indicating an increase in prostate cancer-free survival in the rats assigned to diet restriction (Fig. 3, B). The two factors (diet composition and level of intake) and their interaction term were entered into the Cox model. The interaction term for the type of diet and the amount of dietary intake was not statistically significant (Wald test, P = .38) and was therefore removed from the model. The model results suggest that diet-restricted rats had a statistically significantly lower risk of dying with prostate cancer over their lifespan than ad libitum-fed rats, after controlling for diet type (HR = 0.68 , 95% CI = 0.49 to 0.96; P = .029). ...
Interestingly, no statistically significant interactions were observed between energy intake and diet composition. Thus, tomato products and diet restriction may have additive independent benefits.
Note that bit about "unlimited access to food." In properly-done CR studies, the "AL" group is not strictly "ad libitum," but is slightly restricted to avoid obesity. So in fact this was very, very very mild CR indeed -- 5-10% at most.
And again, there was a slight weight reduction in tomato-fed rats:
... suggesting crypto-CR at work.
