Prof. Dr. Adam Antebi

Research Area: Metabolism, proteostasis, signal transduction


1. Research Background:

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.

2. Research questions addresses by the group:

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 recognitionparticle, 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.

3. Possible projects:

Some of the questions/projects we are pursuing include:

  1. How does nucleolar function impact longevity? Perform genetic screens for regulation of nucleolar markers to find novel regulators of nucleolar function and size.
  2. A HLH transcriptional network governs longevity. So do genes that regulate nucleolar function.
    Do these two processes come together in the process of ribogenesis?
  3. What is the relationship between nucleolar function, nuclear architecture, and epigenetic regulation of longevity?
  4. How might the ribosome affect regulation of proteostasis and neurodegeneration?
  5. How might aspects of RNA metabolism including transcriptional and splicing fidelity affect life span regulation?
  6. How does organellar communication between mitochondria, lysosome and nucleus play out in the health and life of the cell with age?
  7. What specific processes regulated by the HLH transcriptome are crucial to health and long life?
  8. What is the relationship between these convergent mechanisms with immune function?
  9. What is the relationship between metabolism and quality control, especially the links between lipid metabolism and life span? Can the metabolome inform the molecular underpinnings of longevity?
  10. Do the convergent regulators of C. elegans longevity also impact health and life span of vertebrate species, including the killifish Notobranchius furzeri, mouse and humans?

4. Applied Methods and model organisms:

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

5. Desirable skills and qualifications:

Molecular biology and genetics

6. References:

  1. Tiku, V., Kew, C., Mehrotra, P., Ganesan, R., Robinson, N., A. Antebi (2018) Nucleolar Fibrillarin is an evolutionarily conserved regulator of bacterial pathogen resistance. Nat Commun 9(1):3607. doi: 10.1038/s41467-018-06051-1.
  2. Tiku, V., Jain, C., Raz, Y., Nakamura, S., Heestand, B., Liu, W., Späth, M., Suchiman, H., Eka, D., Müller, R.U., Slagboom, P.E., Partridge, L., and Antebi, A. (2017) Small nucleoli are a cellular hallmark of longevity. Nat Commun 8: 16083. doi: 10.1038/ncomms16083.
  3. Nakamura, S., Karalay, Ö., Jäger, P.S., Horikawa, M., Klein, C., Nakamura, K., Latza, C., Templer, S.E., Dieterich, C., and Antebi, A. (2016) Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals. Nat Commun. 7: 10944.
  4. Denzel, M.S., Storm, N.J., Gutschmidt, A., Baddi, R., Hinze, Y., Jarosch, E., Sommer, T., Hoppe, T., and Antebi, A. (2014). Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156, 1167-1178.
  5. Magner, D.B., Wollam, J., Shen, Y., Hoppe, C., Li, D., Latza, C., Rottiers, V., Hutter, H., and Antebi, A. (2013). The NHR-8 nuclear receptor regulates cholesterol and bile acid homeostasis in C. elegans. Cell Metabolism 18, 212-224.
  6. Shen, Y., Wollam, J., Magner, D., Karalay, O., and Antebi, A. (2012). A steroid receptor-microRNA switch regulates life span in response to signals from the gonad. Science 338, 1472-1476.