Research in Dr. Nelson's laboratory is focused on three questions. The first concerns the role of glucocorticoids in the retardation of aging by food restriction. The second seeks to understand the role of insulin in mammalian longevity. The third aims to identify novel mutations that extend mammalian lifespan.

Long-lived chronically food restricted rodents are moderately hyperadrenocortical. This hyperadrencorticism appears to be physiologically significant, because it is associated with a large number of changes consistent with systemic elevation of glucocorticoids including reduced plasma ACTH, attenuated inflammatory responsiveness, and changes in gene expression. Studies are now underway to test more directly the hypothesis that hyperadrenocorticism plays a role in the anti-aging actions of food restriction. Mice genetically deficient in glucocorticoids are being food restricted to determine if the absence of hyperadrenocorticism interferes with the anti-aging actions of food restriction. Ad lib fed mice are receiving glucocorticoid supplementation to determine whether mimicking the hyperadrenocorticism of food restriction results in anti-aging actions.

Moderate hypoinsulinemia in the absence of glucose intolerance is present in most long-lived mammalian models. The goal of a second area of study in the laboratory is to determining whether this hypoinsulinemia directly contributes to extended longevity. Mice deficient in protein-tyrosine-phosphatase 1B (knockout) exhibit enhanced insulin sensitivity for glucose disposal and reduced plasma levels of insulin comparable to those of long-lived food restricted and dwarf mice. These mice are being studied to determine whether they exhibit any of the delayed aging traits of calorie restricted and dwarf models.

Dr. Nelson is also funded as an Ellison Senior Scholar in Aging to probe ENU mutagenized mouse stocks for long-lived mutants. Mutational screens in D. melanogaster and C. elegans demonstrate that single gene mutations can extend life span. The phenotypes associated with these mutations include reduced insulin and/or insulin-like growth factor signaling and increased resistance to oxidative and other life-threatening stressors. Mammalian models of extended life span also show altered insulin/IGF1 signaling and increased stress resistance. In addition, they exhibit reduced body mass. The hypothesis being tested is that genetic screening of young mice for mutants exhibiting these traits will select for genotypes with extended life span. Collaborations are underway with investigators at Baylor Medical College and Oak Ridge National laboratories who have established ENU protocols for creating and identifying both dominant and recessive mutations in mice.