Research Area: Metabolism, Proteostasis and 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:
To unravel convergent mechanisms of longevity, we have performed genetic screens in C. elegans for factors required for life extension across multiple pathways. Additionally, we have used systems biology to identify common transcriptional and metabolomic signatures regulated by various longevity pathways, and dissected their contribution to life span.
From such approaches we have identified a regulatory network of helix-loop-helix (HLH) transcription factors, consisting of the MYC-MONDO complexes, TFEB, and other factors, which promotes longevity1. How this network integrates diverse inputs from various pathways and what outputs are crucial to life span control are currently under investigation. Specifically we have found that communication among different organelles, such as mitochondria, lysosomes, and fat droplets help orchestrate nuclear activities within these networks, and their downstream metabolic outputs required for life span2.
Relatedly, we have identified the nucleolus as a convergence point of life span control, and discovered that small nucleoli are a cellular hallmark of longevity3. Again how various upstream signaling inputs regulate nucleolar function remains enigmatic, and what nucleolar outputs influence longevity are not well understood. The nucleolus is best known as the site of rRNA production and ribogenesis, and we are therefore exploring contributions of ribosomal function and proteostasis to longevity. Additionally, other ribonucleoprotein particles including the spliceosome, signal recognitionparticle, stress granules, and siRNA pathway components are assembled there. Whether and how these other processes affect homeostasis and longevity remains to be determined. Interestingly, the nucleolus and RNA metabolism also contribute to innate immune signaling, and hence we are currently exploring the relationship between immunity, inflammation and aging4,5.
Through high resolution mass spectrometry, we have identified a handful of shared metabolic modules commonly regulated across various longevity pathways. One such module is the one carbon folate cycle6, essential to the production of nucleotides, amino acids, and vitamins, which are important for protein synthesis, epigenetic state, and other crucial processes. Another identified module is related to purine and pyrimidine metabolism. Through genetic manipulation and metabolite supplementation, we are unraveling the causal contributions of these pathways to life span control.
Finally we are very much interested in how diet impacts life span. We are using genetics and systems approaches to understand how diet restricted states, such as fasting and diapause, sustain organismal health, and trigger tissue rejuvenation upon refeeding. We are examining the role of mTOR, TFEB, AMPK, nuclear receptor signaling and other molecules involved in these processes7-10.
3. Possible projects:
Some of the questions/projects we are pursuing include:
- Are specific metabolic modules commonly regulated by various longevity pathways causal for life span control, and if so, can they be manipulated to improve health and life?
- What is the relationship between convergent longevity mechanisms with immune function? What role does innate immune signaling and inflammation play in regulation of life span?
- What are the processes downstream of the nucleolus that regulate aging? How do ribosomal activities affect regulation of proteostasis and neurodegeneration?
- What specific processes regulated by the convergent HLH network are crucial to health and long life? How do signaling inputs coordinate the nuclear activities of this network?
- How does organellar communication between mitochondria, lysosome and nucleolus play out in the health and life of the cell with age?
- How might other aspects of RNA metabolism including transcriptional and splicing fidelity affect life span regulation?
- Do the convergent regulators of C. elegans longevity also impact health and life span of vertebrate species, such as killifish Nothobranchius furzeri, mouse and humans?
- What are the genetic requirements for longevity during fasting states and activities required for rejuvenation?
4. Applied Methods and model organisms:
- Model Organisms:
Caenorhabditis elegans, the turquoise killifish Nothobranchius furzeri , mammalian cell culture, some mouse and human work.
- Methods: Genetics:
microscopy, mass spectrometry, molecular biology, systems biology (transcriptomics, proteomics, metabolomics), biochemistry
5. Desirable skills and qualifications:
Biochemistry, molecular biology and genetics
- Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals. Nakamura, S., Karalay, Ö., Jäger, P.S., Horikawa, M., Klein, C., Nakamura, K., Latza, C., Templer, S.E., Dieterich, C., and Antebi, A. Nat Commun 2016,7: 10944.
NFYB-1 regulates mitochondrial function and longevity via lysosomal prosaposin, Rebecca George Tharyan, Andrea Annibal, Isabelle Schiffer, Raymond Laboy, Ilian Atanassov, Anna Luise Weber, Birgit Gerisch, Adam Antebi, Nature Metabolism. 2020, 2, 387-396.
Small nucleoli are a cellular hallmark of longevity. 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. Nat Commun 2017, 8: 16083. doi: 10.1038/ncomms16083.
Nucleolar Fibrillarin is an evolutionarily conserved regulator of bacterial pathogen resistance. Tiku, V., Kew, C., Mehrotra, P., Ganesan, R., Robinson, N., A. Antebi Nat Commun 2018, 9:3607. doi: 10.1038/s41467-018-06051-1.
Evolutionarily conserved regulation of immunity by the splicing factor RNP-6/PUF60. Kew C, Huang W, Fischer J, Ganesan R, Robinson N, Antebi A. eLife. 2020 Jun 15;9:e57591. doi: 10.7554/eLife.57591. Online ahead of print.PMID: 3253877
Regulation of the one carbon folate cycle as a shared metabolic signature of longevity. Andrea Annibal, Rebecca George Tharyan ,Maribel Schoenewolff, Hannah Tam, Christian Latza, Markus Max Karl Auler, Adam Antebi. BioRxiv 2020.
Hexosamine pathway metabolites enhance protein quality control and prolong life. Denzel, M.S., Storm, N.J., Gutschmidt, A., Baddi, R., Hinze, Y., Jarosch, E., Sommer, T., Hoppe, T., and Antebi, A. Cell 2014, 156, 1167-1178.
HLH-30/TFEB Is a Master Regulator of Reproductive Quiescence. Gerisch B, Tharyan RG, Mak J, Denzel SI, Popkes-van Oepen T, Henn N, Antebi A. Dev Cell. 2020 May 4;53(3):316-329.e5. doi: 10.1016/j.devcel.2020.03.014. Epub 2020 Apr 16.PMID: 32302543
The NHR-8 nuclear receptor regulates cholesterol and bile acid homeostasis in C. elegans. Magner, D.B., Wollam, J., Shen, Y., Hoppe, C., Li, D., Latza, C., Rottiers, V., Hutter, H., and Antebi, A. Cell Metabolism 2013, 18, 212-224.
A steroid receptor-microRNA switch regulates life span in response to signals from the gonad. Shen, Y., Wollam, J., Magner, D., Karalay, O., and Antebi, A. Science 2012, 338, 1472-1476.