Researchers still don't have a complete and clear picture as to how calorie restriction extends life and produces considerable health benefits. At present the research consists of a large bucket of metabolic changes with varying confidence levels in their involvement as longevity-assurance mechanisms. Reduction in visceral fat tissue seems important, as does the chain of events that starts with sensing levels of methionine in the diet, and also upregulation of the cellular housekeeping processes of autophagy.
There is plenty of room yet to raise up previously unexamined changes to a greater level of importance, however, or to argue over which of the presently better known mechanisms provide a greater contribution to the end result. I expect this process of discovery and argument to continue: as this paper indicates, calorie restriction changes an enormous number of discrete elements of metabolism, and most of these elements interact with one another in complex ways within the vast network of change and feedback. There is more than enough work here for another generation of researchers.
Dietary restriction (DR) extends longevity and delays the occurrence and progression of age associated diseases in a range of organisms. The ubiquity of these effects suggests there should be conserved common molecular pathways underlying how animals slow aging in response to DR. Such mechanisms that might be elucidated in model organisms may therefore apply to mammals and even perhaps primates including humans
One approach to discover such underlying mechanisms of longevity assurance is to study age-dependent gene expression in DR relative to normal-diet animals. Perhaps unsurprisingly, a great many genes are seen to differ between these groups and it is likely that only a fraction of these actually participate in the mechanisms that directly confer longevity assurance.
The breadth of overall transcript changes in response to diet is illustrated by meta-analysis of publicly available transcriptional studies. [Researchers] compiled 40 DR gene expression cases in mouse and identified 12,214 differentially expressed genes. Fewer analyses of chronic differences between DR and normal food have been conducted with Drosophila. [Researchers] examined the chronic effect of DR with samples taken at six and eight different age points in the control and DR cohorts respectively over the course of their lifespan. This design identified 2,079 genes whose transcript abundance associated with adult diet.
Besides rapidly adjusting transcript profiles to acute changes in diet, diet switches rapidly alter age-specific mortality. When switched from protein to non-protein diets, the age-specific mortality of formally protein-fed adults quickly adopts the mortality rate and trajectory of a continuously non-protein-fed cohort. Remarkably, when flies are shifted from a rich diet to just a relatively restricted diet, within days the cohort adopts the same trajectory of low age-specific of adults continuously maintained on restricted diet (and vice versa for cohorts switched from restricted to rich diets). These observations suggest that the molecular, cellular and physiological changes caused by DR to extend lifespan must occur within a short time frame after adults experience an alternative diet.