Insight into the mechanism of lifespan extension by dietary restriction

Caloric restriction (CR) is an environmental intervention that substantially extends lifespan. CR slows the pace of aging process, and delays the onset of age-related diseases, viz., cancer, cardiovascular complications, diabetes and neurological deterioration. Molecular mechanism underlying CR-mediated lifespan increase is poorly understood. Studies presented here aimed to investigate possible biochemical pathways that would be altered to translate CR into longer lifespan. Our approach to find such mechanisms was to search for a biochemical explanation for the increased oxidative stress resistance associated with CR treated flies. For this, we explored the affect of CR on the activity of a major antioxidant enzyme, superoxide dismutase (SOD), levels of small molecular antioxidants, and whole genome expression profiles.

The hypothesis of increased lifespan by CR is associated with increased SOD activity was tested in conjunction with long lived insulin signaling mutant, chico¹ flies. We report here that the mechanism of lifespan extension by CR does not involve increased free radical clearance by SOD. There was no change in the activity of SOD with diet or age. However, chico¹ flies expressed higher CuZn-SOD activity compared to wild-type flies indicating that insulin signaling and CR extend lifespan via different mechanisms.

We provide evidence that the major redox buffer glutathione (GSH) is a key metabolite for the lifespan extension by CR. CR increased GSH level and attenuated the age-dependent decrease in GSH level. We further provide evidence that the expression level of cystathionine β-synthase (CBS), the committing enzyme of the transsulfuration pathway increased under CR conditions to increase GSH synthesis. Furthermore, we show that the effect of CR on lifespan is abolished upon blocking the transsulfuration pathway. These results reveal a previously unrecognized biochemical pathway essential for lifespan extension by CR.

To find candidate genes/pathways responsive to CR, we determined the whole genome expression profiles in flies grown in low and normal caloric diets. We showed that CR induced the expression of genes involved in antioxidative defense, protein metabolism, energy metabolism and genomic maintenance.