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Research in the Gill Lab

Overview

In recent years there have been huge advances in our understanding of the aging process and many of these have stemmed from genetic analysis of the nematode Caenorhabditis elegans (C. elegans). Our lab uses an interdisciplinary approach that combines chemical screens, analytical chemistry, biochemistry and genetics to identify small molecule regulators of aging in C. elegans and determine their molecular mechanism of action.  

 Research image

We first used this approach to identify the ligand for an orphan nuclear receptor, DAF-12, and discovered that the sterol acid, cholestenoic acid, can act as a DAF-12 ligand (Gill et al 2004, Held et al 2006), and has similar structure to the endogenous dafachronic acids identified by Motola et al. (2006). 

Role of N-acylethanolamines in C. elegans development and aging

Current work in the lab is focused on studying the roles of N-acylethanolamines (NAEs), which we recently identified in the worm, and appear to be involved in reproductive development as well as influencing lifespan (Lucanic et al 2011). 

N-acylethanolamines are a group of lipid signaling molecules, which includes the mammalian endocannabinoid N-arachidonoyl ethanolamine (AEA, also known as anandamide), that have been implicated in a variety of physiological processes including nutrient sensing and energy balance (Di Marzo, 2005).  NAEs are generated from phospholipid precursors by the action of the enzyme N-acyl phosphatidyl ethanolamine – specific phospholipase D (NAPE-PLD), and their activity is regulated by a hydrolytic enzyme called fatty acid amide hydrolase (FAAH).  Using gas-chromatography – mass spectrometry (GC-MS) we identified a number of different NAEs in lipid extracts from worms (Lucanic et al 2011) including a molecule called eicosapentaenoyl ethanolamide (EPEA) which shares structural similarity with the mammalian endocannabinoid AEA (Figure 1).

Figure:1 Scheme illustrating the biosynthesis and degradation of NAEs and the structure of one of the NAEs found in C. elegans , eicosapentaenoylethanolamide (EPEA).

Figure:1  Scheme illustrating the biosynthesis and degradation of NAEs and the structure of one of the NAEs found in C. elegans , eicosapentaenoylethanolamide (EPEA). 

Inhibition and over-expression of the worm ortholog of FAAH altered NAE levels in a way that suggested that this enzyme in the worm acts to degrade NAEs (Lucanic et al 2011).  We also found that NAE levels are high during normal larval development but are reduced under conditions where the worm enters a long-lived alternate larval stage called the dauer larva.  Interestingly, although levels of all the NAEs were reduced in dauers, supplementation with just EPEA was sufficient to promote reproductive growth (Figure 2).  A role for NAEs in normal growth was further supported by the observation that animals with reduced NAEs, due to over-expression of FAAH, are slow growing. 

Figure 2: High levels of NAEs are found in animals undergoing normal reproductive growth and are low in dauers. Addition of EPEA to the food promoted reproductive growth in animals that would normally form dauers.

 Figure 2: High levels of NAEs are found in animals undergoing normal reproductive growth and are low in dauers.  Addition of EPEA to the food promoted reproductive growth in animals that would normally form dauers.

In mammals, NAEs are involved in nutrient sensing and energy balance (Di Marzo, 2005).  Similarly we found that NAEs are low in starved larvae as well as in adult animals under dietary restriction conditions, suggesting that NAE levels act as a marker of nutrient status in worms (Lucanic et al 2011).  Dietary restriction is a well-known mechanism for extending lifespan in multiple species and we found that the animals that had reduced NAEs due to over-expression of FAAH showed an increased adult lifespan due to a dietary restriction mechanism.  Furthermore, if we exposed worms to dietary restriction conditions but supplemented their diet with EPEA we found that no lifespan extension was observed.  We suggest that EPEA acts as an internal signal of nutritional status and coordinates the organism’s response to changes in food availability.

Ongoing research projects in the lab include:

  1. Defining the biological roles of N-acylethanolamines in C. elegans
  2. Characterization of N-acylethanolamine enzymes in C. elegans
  3. Screens for novel components of N-acylethanolamine signaling pathways
  4. Effect of N-acylethanolamines on worm models of age-related disease
  5. Chemical screens for compounds that affect life history traits related to aging and metabolism
  6. Identification of natural products and endogenous hormones that affect aging and metabolism

References

Di Marzo, V. & Matias, I. Endocannabinoid control of food intake and energy balance. Nature Neurosci. 8, 585–589 (2005).

Gill MS, Held JM, Fisher AL, Gibson BW, Lithgow GJ. Lipophilic regulator of developmental switch in Caenorhabditis elegans. Aging Cell 2004 Dec;3(6):413‐21

Held JM, White MP, Fisher AL, Gibson BW, Lithgow GJ, Gill MS. DAF‐12‐dependent rescue of dauer formation in C. elegans by 25S‐cholestenoic acid. Aging Cell 2006 5(4):283‐91

Lucanic ML, Held JM, Vantipalli MC, Klang IM, Graham JB, Gibson BW, Lithgow GJ, Gill MS. N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans. Nature 2011 473 (7346):226-9

Motola DL, Cummins CL, Rottiers V, Sharma KK, Li T, Li Y, Suino-Powell K, Xu HE, Auchus RJ, Antebi A, Mangelsdorf DJ.  Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell. 2006 Mar 24;124(6):1209-23.

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