Lapierre, Louis et al. (2011) International Worm Meeting "Autophagy links lipid metabolism to longevity in C. elegans."

Gelino, Sara, Lapierre, Louis, Hansen, Malene, Melendez, Alicia

[International Worm Meeting, 2011]

Autophagy is a key biological recycling process with an emerging role in organismal aging, yet the nature of the autophagic cargo recycled during aging is unknown. Recently, autophagy was shown to be able to lipolyze intracellular lipid droplets by a process called lipophagy. We therefore asked whether lipophagy is an important mechanism for longevity. By investigating long-lived C. elegans lacking a germline with increased lipase activity, we find that autophagy and lipolysis, possibly via a process similar to lipophagy, coordinately modulate lifespan extension. Specifically, we find that glp-1 mutants, which lack a germline due to disrupted Notch signaling, displayed increased autophagy, a process that we observe is regulated by the FOXA transcription factor PHA-4. Accordingly, RNAi knockdown of several autophagy genes or pha-4 specifically suppressed the extended longevity of glp-1 mutants. Consistent with these observations, we find that the nutrient sensor TOR, a major upstream regulator of autophagy, is downregulated in response to germline removal. Germline-less animals is also known to overexpress a lipase LIPL-4, which was previously shown to be sufficient to extend C. elegans lifespan. Importantly, we observe that overexpression of LIPL-4 increased autophagy, and autophagy genes were required for lipl-4-mediated longevity. Similar to glp-1 worms, we find that longevity associated with overexpression of LIPL-4 was dependent on pha-4 and on autophagy genes. In addition, RNAi knockdown of autophagy genes or pha-4 in glp-1 animals reduced lipolytic activity, suggesting a coordinate modulation of lipid metabolism as well as aging by autophagy. Taken together, these observations suggest a novel link between autophagy and lipolysis in C. elegans aging. We propose that the extended longevity of germline-deficient animals depends, at least in part, on the redistribution of fatty acids by autophagy. This work was supported by the Ellison Medical Foundation.

Lapierre, Louis R. et al. (2013) International Worm Meeting "HLH-30/TFEB is a conserved regulator of autophagy and modulates longevity in C. elegans."

De Magalhaes Filho, C. Daniel, Chu, Chu-Chiao, McQuary, Philip R., Ong, Binnan, Irazoqui, Javier E., Gelino, Sara, Davis, Andrew, Visvikis, Orane, Lapierre, Louis R., Hansen, Malene, Dillin, Andrew, Chang, Jessica T.

[International Worm Meeting, 2013]

The cellular recycling process of autophagy is emerging as an important conserved modulator of aging. Autophagy is critical for lifespan extension induced by selected genetic mutations or by nutrient deprivation in C. elegans, but the mechanism(s) by which this occurs remains unclear. Although several transcription factors such as DAF-16/FOXO and PHA-4/FOXA are known to promote longevity, no single transcription factor has been shown to regulate autophagy in these long-lived C. elegans models. Here we show that the C. elegans helix-loop-helix transcription factor HLH-30, a predicted ortholog of the mammalian transcription factor EB (TFEB), not only regulates autophagy but also plays a critical role in lifespan extension. We found that, similar to TFEB, HLH-30 translocates to the nucleus via a mechanism dependent on the conserved autophagy regulator and longevity determinant TOR, where it modulates the expression of multiple autophagy-related genes. Consistent with a role for autophagy in aging, overexpression of HLH-30 extends lifespan and hlh-30 is required for the long lifespan of all known autophagy-dependent longevity models in C. elegans, including dietary restriction. Similarly, we see Tfeb expression upregulated and nuclear localized in liver of dietary-restricted mice, raising the possibility that HLH-30/TFEB influences lifespan in a conserved manner by inducing autophagic flux. Our results thus demonstrate a conserved role for TFEB in regulating autophagy and identify HLH-30 as a novel longevity-modulating transcription factor.

Hresko MC et al. (1994) Worm Breeder's Gazette "Shoot First, Ask Questions Later"

Shrimankar PV, Hresko MC, Waterston RH

[Worm Breeder's Gazette, 1994]

Shoot First, Ask Questions Later M.C Hresko, P.V. Shrimankar and R.H. Waterston. Washington Univ. Sch. of Med., St. Louis, MO 63110. coutu@sequencer.wustl.edu and pvs@elegans.wustl.edu

Wong, Shiquan et al. (2021) International Worm Meeting "Neuronal HLH-30/TFEB Regulates Longevity and Heat Stress Resistance Via Distinct Non-Cell Autonomous Mechanisms"

Lapierre, Louis, Wong, Shiquan, Ryan, Catherine

[International Worm Meeting, 2021]

Transcription factor EB (TFEB) is the central transcriptional activator of the autophagy-lysosomal pathway and is important for organismal lifespan regulation and stress resistance. However, the tissue-specific autonomous and non-autonomous mechanisms orchestrated by TFEB are not well understood. As neurons constitute an important tissue for coordinating organism-wide processes, we investigated the neuronal role of TFEB in stress resistance and longevity. To this end, the C. elegans TFEB orthologue, hlh-30, was pan-neuronally expressed against a ubiquitous hlh-30 loss-of-function background. Findings indicated that while neuronal HLH-30/TFEB is important for the enhanced longevity of daf-2 insulin/insulin-like growth factor receptor signaling (IIS) mutants, it was insufficient to extend the shortened lifespan of hlh-30 loss-of-function mutants. Surprisingly, neuronal HLH-30/TFEB reconstitution mediated robust improvements in thermoresistance in hlh-30 but not daf-2 mutants, suggesting divergent mechanisms of longevity and thermoprotection that can be decoupled with the IIS pathway. Since DAF-16/FOXO is the primary transcription factor responsible for the extended lifespan and improved thermotolerance of daf-2 IIS mutants, we sought to investigate its non-cell autonomous requirement for neuronal HLH-30/TFEB-mediated longevity and thermoresistance. Preliminary findings suggest a synergism of neuronal HLH-30/TFEB with non-neuronal DAF-16/FOXO in lifespan extension but not thermoresistance. Instead, the uncharacterized gene W06A11.1 was identified as a bona fide mediator of thermoresistance which is non-cell autonomously required by neuronal HLH-30/TFEB for effecting thermoprotection. Taken together, these findings indicate a decoupling of the longevity and thermoprotective mechanisms of neuronal HLH-30/TFEB. As TFEB is an emergent target for the treatment of neurodegenerative and age-related diseases, findings herein reveal novel and potentially targetable TFEB-associated mechanisms.

Consortium TCeGS (1994) Worm Breeder's Gazette "The C. elegans Genome Sequencing Project: A Progress Report."

Consortium TCeGS

[Worm Breeder's Gazette, 1994]

The C. elegans genome sequencing project: A progress report. The C. elegans Genome Consortium, Genome Sequencing Center, Washington University School of Medicine, St. Louis, Missouri, USA and Sanger Centre, Hinxton Hall, Cambridge, UK.

McCarter JP et al. (1994) Worm Breeder's Gazette "Somatic Regulation of Germ-line Development. Introduction and Part I; Mitotic Proliferation"

Schedl TB, McCarter JP

[Worm Breeder's Gazette, 1994]

Somatic Regulation of Germ-line Development Introduction, and Part I; Mitotic Proliferation Jim McCarter and Tim Schedl. Dept. of Genetics, Washington Univ. School of Medicine, St. Louis, MO 63110, jim@wugenmail.wustl.edu

Consortium TCeGS (1994) Worm Breeder's Gazette "The C. elegans Genome Sequencing Project: A Progress Report"

Consortium TCeGS

[Worm Breeder's Gazette, 1994]

The C. elegans genome sequencing project: A progress report. The C. elegans Genome Consortium, Genome Sequencing Center, Washington University School of Medicine, St. Louis, Missouri, USA and Sanger Centre, Hinxton Hall, Cambridge, UK.

McCarter JP et al. (1994) Worm Breeder's Gazette "Part II; Non-Autonomy of Hermaphrodite Germ-line Sex Determination"

McCarter JP, Schedl TB

[Worm Breeder's Gazette, 1994]

Somatic Regulation of Germ-line Development, Part II; Non-Autonomy of Hermaphrodite Germ-line Sex Determination Jim McCarter and Tim Schedl. Dept. of Genetics, Washington Univ. School of Medicine, Sl. Louis, MO 63110, jim@wugenmail.wustl.edu

Kitamura S et al. (1994) Worm Breeder's Gazette "The Troponin C Gene, tnc-1, of Caenorhabditis elegans: Genome Structure and Mutation Sites of pat-10"

Williams BD, Kitamura S, Kagawa H, Sakube Y, Matsumoto S

[Worm Breeder's Gazette, 1994]

The troponin C gene, tnc-1 of Caenorhabditis elegans: Genome structure and mutation sites of pat-10 S. KITAMURA, B. WILLIAMS*, Y. SAKUBE, S. MATSUMOTO and H. KAGAWA, Dept. of Biol., Fac. of Sci., Okayama University, Japan, 700. *;Dept. of Gen., Washington Univ. School of Med., St. Louis

Gelino, Sara et al. (2009) International Worm Meeting "Role of autophagy in C. elegans longevity pathways."

Lapierre, Louis, Ong, Binnan, Hansen, and Malene, Gelino, Sara, McQuary, Philip

[International Worm Meeting, 2009]

C. elegans lifespan is modulated by multiple genetic pathways and processes. These include the DAF-2/insulin/IGF-1-like and TOR pathways, dietary restriction, protein translation and mitochondrial activity (reviewed in 1). Whereas our molecular understanding of these pathways comprises intricate roles for multiple transcription factors, including the transcription factors DAF-16/FOXO, PHA-4/FOXA, SKN-1 and HSF-1 (2, 3), much less is known about the downstream cellular events. The cellular process of autophagy has recently been linked to aging in C. elegans. During autophagy, cytoplasm and organelles in the cell is degraded and recycled (4). We and others have shown that autophagy is required for at least some of the known C. elegans longevity pathways (see references in 1). For example, autophagy genes are essential for the long life of dietary-restricted animals and these animals have increased levels of autophagy. In contrast, autophagy does not appear to play a critical role in the extended lifespan observed in animals with mutations in genes involved in protein translation (5). We have continued to investigate the role of autophagy in the known longevity pathways in C. elegans. For example, we find that the autophagy gene bec-1, the worm ortholog of the yeast and mammalian autophagy gene ATG6/VPS30/beclin 1, affects specific stress responses frequently observed in long-lived animals, such as thermotolerance. These results, along with our efforts to better characterize autophagy in C. elegans, will be discussed. 1. Melendez, Hall and Hansen, Methods Enzymol, 2008 2. Kenyon, Cell, 2005 3. Mair and Dillin, Annu Rev Biochem, 2008 4. Levine and Kroemer, Cell, 2008 5. Hansen et al., PLoS Genetics, 2008.