Areas of Focus

The Ghazi Lab is currently focused on the following three key areas of research.

Transcription Factors that Mediate Signals From Reproductive Cells to Modulate Aging

While it is well recognized that increasing age impairs reproductive fitness, how the germline of an animal influences aging of its somatic cells is not known. Recent discoveries in worms, flies and mice have shown that signals from reproductive tissues indeed influence the length and quality of life of the whole organism.

In C. elegans, removal of a population of germline-stem cells (GSCs) extends lifespan and enhances stress resistance. These changes appear to be brought about by activation of a network of transcription factors in the intestinal cells. We have identified a group of such factors, and our current research focuses on three such conserved proteins:

1. NHR-49, a nuclear receptor that is the worm functional homolog of vertebrate PPARα protein, a major target for drugs against metabolic disorders
2. TCER-1, the worm homolog of a human transcription elongation and splicing factor, TCERG1
3. DAF-16, a longevity determinant whose human homolog, FOXO3A, has been implicated in human aging

We use these factors as tools to decipher the genetic network that extends lifespan in response to reproductive stimuli, using a combination of molecular genetic and genomic techniques.

The Role of Fat Metabolism in Reproduction and Aging

GSC-less mutants accumulate excessive lipids but are still long lived. The mechanisms underlying this ‘healthy obesity’ are unknown and intriguing. Germline loss is a major metabolic challenge that compels the animal to stop fat deposition into eggs and remodel its lipid reserves. Hence, these ‘healthy obese’ mutants are a valuable model to understand how lipid homeostasis is achieved following changes in procreation and age. Our recent studies have shown that the transcription factors, NHR-49/PPARα, DAF-16/FOXO3A and TCER-1/TCERG1, together activate both lipid anabolic and catabolic pathways in GSC-less mutants, and this concomitant augmentation is essential for longevity. Our current efforts are focused on understanding how these ostensibly antagonistic processes are simultaneously activated and how animals coordinate the production and breakdown of lipids.

Proteasomal Regulation of Aging

The programmed destruction of regulatory proteins by the proteasome pathway is widely used for controlling many important biological processes including aging. Previously, we discovered that the proteasomal pathway regulates aging in C. elegans. In mutants of the insulin/IGF-1 receptor daf-2, which live twice as long as normal worms, proteasomal E3 ligases are recruited for the ubiquitination and likely degradation of cellular proteins that inhibit longevity. Current efforts are focused on the identification of such E3 ligase substrates whose degradation is essential for lifespan extension.