University of Pittsburgh School of Medicine - Interdisciplinary Biomedical Graduate Program
Aging is an inescapable reality of our lives and a fascinating biological process. With a rapidly aging global population, aging is a major public-health issue. In the last two decades, an overwhelming body of evidence has demonstrated that aging is a genetically regulated process. Alterations in single genes can produce dramatic increases in the lifespan of various species such as worms, flies and mice. Most interestingly, the human counterparts of genes that influence aging in model organisms have been found to be associated with extraordinary human longevity in multiple racial backgrounds.
In the Ghazi lab, we use the well-known model, Caenorhabditis elegans, to identify and study genes that influence aging. A major focus of our research is genes that govern the relationship between reproduction and aging. In C. elegans, removal of a pool of germline-stem cells triggers the activation of a network of transcription factors that mediate a dramatic increase in the animal’s lifespan and healthspan. The Ghazi lab has focused on how this transcriptional network promotes longevity. In studying three of these conserved factors, DAF-16 (homolog of human FOXO3A), TCER-1 (homolog of human TCERG1) and NHR-49 (functional homolog of human PPARa), we have discovered that fat metabolism is significantly modified to promote longevity. In particular, these proteins appear to coordinately enhance lipid production and breakdown to retain lipid homeostasis. Our current efforts are aimed at understanding how lipid anabolism and catabolism are balanced and why this balance is important for health.
We are also interested in post-translational cellular events that influence how long an organism lives. In particular, we study the impact of the proteasomal pathway of protein degradation on lifespan. Proteasomal E3 ligases determine which cellular proteins get tagged with a small protein called Ubiquitin and consequently, often get destined for degradation. Earlier, we had identified specific E3 ligases that are essential for the extended lifespan of mutants of the insulin/IGF-1 receptor, DAF-2. In worms and in many other organisms, impaired insulin/IGF-1 signaling increases lifespan dramatically and we found this to depend on specific members of the CUL-1/SCF E3 ligase complex. We are now studying these E3 ligases to identify their substrates and discover proteins whose destruction is important for lifespan benefits.