Life-long dietary restriction can delay age-related impairments and extend lifespan. However, life-long dietary restriction itself would not be a practical intervention in humans. Therefore many investigators are studying the mechanism by which dietary restriction produces its beneficial effects, with the goal of activating these mechanisms by pharmacological interventions.
Of particular value would be an intervention that would not require life-long treatment but that would actually reverse age-related impairments even if given only late in life. The goal of the present project is to test if production of low blood glucose or interfering with glucose metabolism, by exaggerating an important characteristic of caloric restriction, will reverse age-related impairments. The project would also examine in more detail the molecular mechanisms by which caloric restriction extends lifespan.
The rationale for our project is based on a number of published results but primarily on our own observations regarding the regulation of gene expression by caloric restriction and glucose. We and others have long hypothesized that at least some of the beneficial effects of caloric restriction are mediated by a reduction in blood glucose (opposite of the harmful effects of high blood glucose in diabetes).
A related hypothesis suggested by E. Masoro is that caloric restriction extends lifespan by altering ìcharacteristics of glucose fuel useî but the nature of this change has not been determined. We have now found that production of very low blood glucose by insulin injection produces a profile of gene expression very similar to that produced by caloric restriction. In particular, based on the profile of expression of genes that regulate glucose metabolism, both caloric restriction and low blood glucose change the way glucose is broken down to make energy.
Specifically, low blood glucose actually reduces the use of glucose to make energy, and routes the glucose toward making anti-oxidant molecules. The net outcome of these effects is that low blood glucose, like caloric restriction, produces a highly anti-oxidative state, the opposite of the highly oxidative state produced by diabetes. Furthermore, the logic of this regulation suggests that each time the metabolic genes are exposed to relatively high glucose after a meal, the gene expression profile becomes increasingly likely to remain in the pro-oxidant state.
This could explain why cellular oxidation and associated impairments increase progressively with age. On the other hand, the same logic suggests that extremely low glucose, lower than can be obtained by caloric restriction, or interference with glucose metabolism could actually ìresetî the profile of gene expression toward an anti-oxidative state. To the extent that oxidative damage drives age-related pathologies, this suggests that very low blood glucose or reduced glucose metabolism, even if instituted only temporarily late in life, may actually reverse age-related impairments including cellular oxidation and cancer burden and extend lifespan.
Our project will test this hypothesis in both aging mice and in aging nematodes. The role of specific glucose-regulated genes in mediating effects of caloric restriction will also be tested.