All:
It's often been argued that CR works primarily through GH/IGF-1 signaling, and that we should therefore not do anything (such as consuming relatively high-protein diets) that might keep our IGF-1 levels up. This, despite the fact that a good GH/IGF-1 signaling mutant rodent study shows that the life-extending, youth-preserving action of CR does not work (or certainly does not work primarily) through a reduction in IGF-1 signaling, and, more importantly, the HUGE amount of evidence that CRed animals do as well or better on a high- as vs a low-protein diet any case (some documentation also in op cit post).
Some months back another mutant-mouse +/- CR study (1) was posted (to no commentary) on the CR list, which demonstrates the disconnect between GH/IGF-1 signaling even more directly than the first study linked above, especially for anyone digging into the full text; I highlight that study here.
Rats were fed normally or with a 30% calorie-restricted diet for 24-26 months. The kidneys of male wild-type young (6 months) and old (24-26 months) rats were compared with male hemizygote transgenic young (6 months) and old (24-26 months) rats ["with suppressed GH activity through ... an antisense GH transgene"] fed with either regular diet or 30% calorie-restricted diet for their entire life span.
RESULTS: The transgenic rats had relatively less pituitary GH-secreting cells, and the plasma levels of IGF-1 were decreased by 53% in homozygote rats (tg/tg) and by 28% in hemizygote rats (tg/wt)... [83% of] Wild-type rats fed the regular diet developed age-associated nephropathy ... In contrast, only 26% of the naturally surviving hemizygote rats showed features of nephropathy, despite the fact that these rats lived 8% longer (maximum survival 171 weeks) ...
When chronic suppression of GH/IGF-1 activity was combined with lifelong caloric restriction, however, age- associated nephropathy was nonexistent in hemizygote transgenic rats, and they showed about 30% increase in survival (maximum survival 204 weeks). There was no significant difference in the rate of neoplastic or nonneoplastic lesions (other than in the kidney) in the regularly fed wild-type rats or in the calorie-restricted hemizygote transgenic rats that survived longer.... (1)
Combining the paper's Tables 2 and 3, for wild-type (WT) and hemizygous-transgenically GH suppressed (TG) ad lib and CR animals, without the standard deviations, yields (sorry if this is hard to read):
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Group |IGF-1 @ 6 mo | @ 24-26 mo |Max LS (weeks)| % Increase
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Wild AL 1,613.6 1,230.2 158 n/a
TG AL 1,172.2 1,362.3 171 8.2
Wild CR 1,415.8 1,152.4 194 22.7
TG CR 808.2 613.4 204 29.1
So: relative to a nicely longevous wild-type, AL control group, a targeted reduction in GH/IGF-1 (as opposed to Ames dwarf mice, which have reductions in IGF-1, thyroid hormones, and prolactin) increases lifespan by just 8%. Moderate (30%) CR in animals with normal GH expression and translation leaves them with similar or slightly higher IGF-1 levels compared with the transgenic mice, but they live considerably longer (22.7% extension). And while adding GH suppression to CR lowers IGF-1 DRAMATICALLY, it only slightly further extends their lifespan.
This is consistent with, but even clearer than, the similar results in GHR knockout mice, linked above. Suppressed IGF-1 signaling likely plays some role in the effect of CR -- but it's a minor contributor, not a dealbreaker.
-Michael
1. Am J Nephrol. 2008;28(5):755-64.
Genetic suppression of GH-IGF-1 activity, combined with lifelong caloric restriction, prevents age-related renal damage and prolongs the life span in rats.
Zha Y, Taguchi T, Nazneen A, Shimokawa I, Higami Y, Razzaque MS.
PMID: 18434714 [PubMed - indexed for MEDLINE]
