Our interest is in the beneficial effects of dietary restriction on health in mammals. In models organisms from yeast to rodents, these benefits include extended longevity, improved healthspan and increased resistance to stress. Dietary restriction comprises a variety of feeding regimes focused either on reducing total calorie intake (calorie restriction) or enforced periods of fasting between meals (intermittent fasting; e.g. every-other-day fasting). Although dietary restriction was first observed to extend longevity in rats in the 1930s, the components of an optimally beneficial diet remain controversial. Furthermore, our understanding of the molecular mechanisms underlying such benefits is far from complete, particularly in mammals due to the enormous cost of lifespan studies and the lack of any reductionist systems in which to rigorously test competing hypotheses.
A strong candidate which encompasses much of the existing experimental evidence is the hormesis hypothesis of dietary restriction. This hypothesis postulates that dietary restriction is a mild stress to which cells/organisms adapt by upregulating endogenous protective mechanisms. One major implication is that the benefits of dietary restriction on lifespan and acute stress resistance are manifestations of a common underlying mechanism, the adaptive response to stress.
Experiments in the Mitchell lab are focused on nutritional and genetic determinants of adaptive stress resistance and its potential beneficial applications in humans. We use resistance to acute organ stress associated with surgical ischemia reperfusion injury as a readout of protection. We are characterizing two novel ways to induce protection: food restriction and DNA damage. Previously it was shown that mice with inborn deficiencies in the ability to repair particular types of endogenous DNA damage activate an adaptive stress response similar to that of dietary restriction. If the benefits of dietary restriction are apparent as rapidly in mammals as they are in lower organisms, this would then suggest the exciting possibility of using short-term dietary interventions not only for elucidating underlying mechanisms of protection in mammals, but also for practical applications in the clinic.