Our research program focuses upon two major areas dealing with the molecular biology and molecular genetics of aging and longevity. Our approach to these projects is through the use of state-of-the-art molecular probes in combination with transgenic and knockout mouse models. First, our Program Project focuses upon the regulation of stress response genes and the signaling cascades that target these genes in eukaryotic tissues (liver, brain, and muscle). We have shown that aging results in the development of a state of chronic inflammatory stress and that this occurs in the absence of an inflammatory challenge, such as bacterial lipopolysaccharide (LPS) and mitochondrial damaging agents that generate ROS, such as 3-nitropropionic acid. In addition, aging tissues exhibit a prolonged response to these inflammatory agents, suggesting that the ability to recover from an inflammatory challenge is age related.
Our goal is to understand the mechanism of these age-associated changes in gene regulation and signaling cascade activities that lead to the chronic inflammation and to the decreased ability to recover from inflammatory stress. Presently, our research focuses upon whether protein structural changes due to protein modifications (phosphorylation) in aged tissues affect protein-protein interactions and kinase activities thereby altering the processes of signal transduction and the regulation of targeted stress response genes.Our second program focuses upon understanding the molecular genetic basis of determination of longevity of the Snell dwarf and Ames dwarf mice. These mice have (a) mutations of the either Pit-1 or Prop-1 loci, respectively, that result in failure of development of somatotropes (GH), thyrotropes (TSH) and lactotropes (prolactin) of the anterior pituitary, and (b) live approximately 40-60% longer than normal.We hypothesize that the GH deficiency, which results in non-fasted decrease of circulating insulin/IGF-1levels, is a factor in the decreased function of the insulin/IGF-1 signaling pathway; (b) that these mutants exhibit characteristics similar to the those caused by the weak mutation of daf-2, age-1, or daf-16 loci that result in the increased life span of the nematode, C. elegans; (c) that attenuation of this pathway in the mouse mutants, as in the nematode, decreases oxidative stress and favors the development of resistance to oxidative stress, both of which correlate with longevity.Our goal, is to demonstrate that the molecular and genetic mechanisms of attenuation of the insulin/IGF-1 pathway in the mouse mutants are the basis for development of the molecular genetic program of longevity of these mice. In summary, our overall working hypothesis states that oxidative stress is a major factor in the development of age-associated biochemical phenotype and age-associated diseases and that determination of longevity involves a complex genetic program activated during the early phases of maturation growth that slows down the development of aging biochemical characteristics.