Calorie restriction (CR) has been shown to extend life and confer a variety of salutary effects in a wide range of organisms. While some of the genetics of the pathways have been worked out, the connection between CR and molecular signaling pathways remains murky. In particular, it remains to be seen whether CR’s effects are mediated by global changes in energy budget, or whether (as suggested by the results of single-amino-acid deprivation as in methionine restriction) the critical upstream event is a shortage of some specific molecule(s) concomitant with overall dietary restriction.

Simpson and Raubenheimer review the observations and concepts that underlie this controversy, and propose a statistical framework for deconvolution of micronutrients and global energy intake:

Caloric Restriction and Aging Revisited: The Need for a Geometric Analysis of the Nutritional Bases of Aging

One of the most important findings in the field of the biology of aging has been the demonstration that modest dietary restriction extends life span in a wide range of taxonomically disparate organisms. There is currently a debate as to whether longevity is prolonged because of caloric restriction or due to more specific nutrient effects. Recent advances in nutritional research, notably the development of state–space geometric models, the Geometric Framework (GF), offer new opportunities to disentangle the effects of calories and nutrients. We begin by introducing these models, then set out the four questions that must be addressed to establish the relationship between nutrition and aging and indicate how the GF might help in answering these. We next provide an exemplar experimental protocol and consider some practical challenges to implementing the GF. Our conclusion is that Drosophila provides the most suitable system for an initial study.

By the way, these authors are among that rare breed who work in multiple organisms (from desert locusts to fish), so that last sentence of the abstract isn’t one of those totally self-serving moments where a researcher reviews the literature and finds — surprise! — that their model system is the perfect one for advancing a given field.