The Rieske oxygenase DAF‐36 functions as a cholesterol 7‐desaturase in steroidogenic pathways governing longevity

Abstract

Summary Bile acids are cholesterol-derived signaling molecules that regulate mammalian metabolism through sterol-sensing nuclear receptor transcription factors. In C. elegans, bile acid-like steroids called dafachronic acids (DAs) control developmental timing and longevity by activating the nuclear receptor DAF-12. However, little is known about the biosynthesis of these molecules. Here we show that the DAF-36/Rieske oxygenase works at the first committed step, converting cholesterol to 7-dehydrocholesterol. Its elucidation as a cholesterol 7-desaturase provides crucial biochemical evidence that such oxygenases are key steroidogenic enzymes. By controlling DA production, DAF-36 regulates DAF-12 activities for reproductive development and longevity, and may illuminate related pathways in metazoans.

Mutation of C. elegans demethylase spr-5 extends transgenerational longevity

“…DAF-36 is required for the production of the DAF-12 activating steroid dafachronic acid [27,28]. Consistently, we found that late generation spr-5(by101) mutant worms treated with daf-36 RNAi eliminated the trans-generational lifespan extension (Figure 3D, two-way ANOVA P < 0.0001).…”

“…DAF-12 is a nuclear hormone receptor, which has been shown to be necessary for the longevity extension regulated by a germline to soma longevity signaling pathway [25]. DAF-12 is activated by the steroid dafachronic acid [26], which is synthesized from exogenous cholesterol by a complex biosynthesis process whose first committed step requires the Rieske oxygenase, DAF-36 [27][28][29]. A second major germline to soma signaling pathway that regulates longevity has been reported, which culminates with the transcription factor DAF-16/FOXO [9,30].…”

Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes

“…It has been proposed that DAF-9 is the worm ortholog of mammalian CYP27A (1), a cytochrome P450 enzyme that catalyzes consecutive hydroxylations of substrate and acts at the late stage of bile acid production (3). DAF-36 is postulated to work at the earlier step of ⌬7-DA production as a Rieske-like oxygenase, followed by the potential reductases and dehydrogenases to produce DA precursors (2,4).…”

Empirical Validation of a Hypothesis of the Hormetic Selective Forces Driving the Evolution of Longevity Regulation Mechanisms

“…A body of evidence indicates that endogenous and exogenously added bile acids can extend healthy lifespan in laboratory mammals and nematodes (Amador-Noguez et al, 2004, 2007; Motola et al, 2006; Gems, 2007; Gerisch et al, 2007; Russell and Kahn, 2007; Gems and Partridge, 2008; Ramalho et al, 2008; Thomas et al, 2008; Amaral et al, 2009; Hylemon et al, 2009; Lefebvre et al, 2009; Monte et al, 2009; Tiwari and Maiti, 2009; Vallim and Edwards, 2009; Goldberg et al, 2011, 2013; Pols et al, 2011; Wollam et al, 2011, 2012; Lee and Schroeder, 2012; Chiang, 2013; de Aguiar Vallim et al, 2013; Groen and Kuipers, 2013; Li and Chiang, 2013, 2014; Magner et al, 2013; Arlia-Ciommo et al, 2014b; Mahanti et al, 2014). Bile acids are beneficial to health and longevity of animals not only because they accelerate the emulsification and absorption of dietary lipids and fat-soluble vitamins, affect the composition and proliferation of the intestinal microbial flora, and support the maintenance of organismal sterol homeostasis (Thomas et al, 2008; Amaral et al, 2009; Hylemon et al, 2009; Lefebvre et al, 2009; Monte et al, 2009; de Aguiar Vallim et al, 2013).…”

“…Bile acids are beneficial to health and longevity of animals not only because they accelerate the emulsification and absorption of dietary lipids and fat-soluble vitamins, affect the composition and proliferation of the intestinal microbial flora, and support the maintenance of organismal sterol homeostasis (Thomas et al, 2008; Amaral et al, 2009; Hylemon et al, 2009; Lefebvre et al, 2009; Monte et al, 2009; de Aguiar Vallim et al, 2013). Bile acids extend healthy lifespan in animals also because they act as signaling molecules that enable to sustain lipid, glucose, and energy homeostasis (Motola et al, 2006; Gerisch et al, 2007; Russell and Kahn, 2007; Ramalho et al, 2008; Thomas et al, 2008; Amaral et al, 2009; Hylemon et al, 2009; Lefebvre et al, 2009; Monte et al, 2009; Tiwari and Maiti, 2009; Vallim and Edwards, 2009; Goldberg et al, 2011, 2013; Pols et al, 2011; Wollam et al, 2011, 2012; Lee and Schroeder, 2012; Chiang, 2013; de Aguiar Vallim et al, 2013; Groen and Kuipers, 2013; Li and Chiang, 2013; Magner et al, 2013; Arlia-Ciommo et al, 2014b; Mahanti et al, 2014). Moreover, bile acids extend healthy lifespan in animals because these mildly toxic molecules with detergent-like properties can activate detoxification of xenobiotics, thus promoting chemical hormesis and operating as endobiotic regulators of aging that improve health and prolong longevity (Amador-Noguez et al, 2004, 2007; Gems, 2007; Russell and Kahn, 2007; Gems and Partridge, 2008; Burstein et al, 2012a; Arlia-Ciommo et al, 2014b; Li and Chiang, 2014; Medkour and Titorenko, 2016).…”