A couple of recent papers on calorie restriction caught my eye today - the standard fare for recent investigations, containing a little clarification, a little muddying of the waters. The behavior of metabolism is complex indeed, not to mention the large differences between species. All sorts of genes, mechanisms and pathways are involved in calorie restriction, and scientists are still in that portion of the discovery process that produces apparently contradictory information.
First off, a little more support for the interesting biomechanisms of calorie restriction - going beyond the benefits of less visceral fat - to be triggered by less methionine in the diet:
Dietary restriction (DR) lowers mitochondrial reactive oxygen species (ROS) generation and oxidative damage and increases maximum longevity in rodents. Protein restriction (PR) or methionine restriction (MetR), but not lipid or carbohydrate restriction, also cause those kinds of changes. However, previous experiments of MetR were performed only at 80% MetR, and substituting dietary methionine with glutamate in the diet.
In order to clarify if MetR can be responsible for the lowered ROS production and oxidative stress induced by standard (40%) DR, Wistar rats were subjected to 40% or 80% MetR without changing other dietary components. It was found that both 40% and 80% MetR decrease mitochondrial ROS generation and percent free radical leak in rat liver mitochondria, similarly to what has been previously observed in 40% PR and 40% DR.
The results show that 40% isocaloric MetR is enough to decrease ROS production and oxidative stress in rat liver. This suggests that the lowered intake of methionine is responsible for the decrease in oxidative stress observed in DR.
Can human studies be too many years away? I imagine that producing a safe diet with much lower levels of methionine is not impossible, and that people out there in the calorie restriction community will hack away at that problem with more enthusiasm as the evidence mounts.
The second paper adds some additional facts and confusion to discussion of the role of autophagy in calorie restriction, and draws in other work on the TOR gene and calorie restriction.
In many organisms, dietary restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles.
In this study, we asked whether autophagy might contribute to the lifespan extension induced by dietary restriction in C. elegans. We find that dietary restriction and TOR inhibition produce an autophagic phenotype and that inhibiting genes required for autophagy prevents dietary restriction and TOR inhibition from extending lifespan. The longevity response to dietary restriction in C. elegans requires the PHA-4 transcription factor. We find that the autophagic response to dietary restriction also requires PHA-4 activity, indicating that autophagy is a transcriptionally regulated response to food limitation.
In spite of the rejuvenating effect that autophagy is predicted to have on cells, our findings suggest that autophagy is not sufficient to extend lifespan. Long-lived daf-2 insulin/IGF-1 receptor mutants require both autophagy and the transcription factor DAF-16/FOXO for their longevity, but we find that autophagy takes place in the absence of DAF-16. Perhaps autophagy is not sufficient for lifespan extension because although it provides raw material for new macromolecular synthesis, DAF-16/FOXO must program the cells to recycle this raw material into cell-protective longevity proteins.
It seems to me that a pressing next step in understanding the biomechanisms of calorie restriction is a definitive account of how autophagic and mitochondrial changes brought on by CR are linked.