Research Area: Metabolism, proteostasis, signal transduction
Over the last several decades, studies in model genetic organisms have revealed that animal longevity is plastic and regulated by evolutionarily conserved metabolic signaling pathways. These pathways include reduced insulin/IGF and mTOR signaling, reduced mitochondrial function, dietary restriction mediated longevity, and signals from the reproductive system, which act through specific constellations of transcription factors to extend life. Whether they converge on common regulators or shared downstream processes, however, has remained largely an open question. Deciphering convergent mechanisms is important because it may allow us to understand what lies at the heart of longevity and identify critical targets to extend health and life.
What are the convergent mechanisms of longevity? What are the core processes for life span control? My laboratory has taken a multipronged approach to address these key questions. First, we have performed genetic screens in C. elegans for factors required for life extension across multiple pathways. Second, we have used systems biology to identify common transcriptional signatures regulated by various longevity pathways, and dissected their contribution to life span. From such approaches we have identified an extensive helix-loop-helix (HLH) transcription factor network, consisting of the MYC-MONDO complex and TFEB, which promotes longevity. Among other things, this network largely regulates metabolism of lipids, carbohydrates, amino acids, amines, nucleosides, and mitochondria, but how these processes actually relate to life span remains to be elucidated. In addition, we have identified the nucleolus as a central convergence point of longevity regulation and found a number of genes involved in the regulation of nucleolar size. In particular we have discovered that small nucleoli are a cellular hallmark of longevity, but what this means mechanistically is unclear. The nucleolus is best known as the site of rRNA production and ribogenesis, and we are therefore exploring contributions of ribosomal function to longevity. Additionally, the nucleolus is the locus of assembly for other ribonucleoprotein particles including the spliceosome, signal recognition particle, telomerase, stress granules, and siRNA pathways. Whether and how these other processes affect homeostasis and longevity remains to be determined. A unifying hypothesis is that metabolic processes impinge on the fidelity of ribonucleoprotein assembly and activity in the nucleolus. This ramifies to affect major information processing pathways in the cell--replication, epigenetic transmission, transcription, splicing, translation, and protein quality control--and thereby cellular homeostasis.
Some of the questions/projects we are pursuing include:
Model Organisms: the roundworm Caenorhabditis elegans, mammalian cell culture, the turquoise killifish Notobranchius furzeri
Methods: Genetics, microscopy, mass spectrometry, molecular biology, systems biology (transcriptomics, proteomics, metabolomics), biochemistry