A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling

Abstract

Broad aspects of Caenorhabditis elegans life history, including larval developmental timing, arrest at the dauer diapause, and longevity, are regulated by the nuclear receptor DAF-12. Endogenous DAF-12 ligands are 3-keto bile acid-like steroids, called dafachronic acids, which rescue larval defects of hormone-deficient mutants, such as daf-9/cytochrome P450 and daf-36/Rieske oxygenase, and activate DAF-12. Here we examined the effect of dafachronic acid on pathways controlling lifespan. Dafachronic acid supplementation shortened the lifespan of long-lived daf-9 mutants and abolished their stress resistance, indicating that the ligand is ''proaging'' in response to signals from the dauer pathways. However, the ligand extended the lifespan of germ-line ablated daf-9 and daf-36 mutants, showing that it is ''antiaging'' in the germ-line longevity pathway. Thus, dafachronic acid regulates C. elegans lifespan according to signaling state. These studies provide key evidence that bile acid-like steroids modulate aging in animals.aging ͉ DAF-12 ͉ hormone ͉ dafachronic acid ͉ germ-line longevity E ndocrine systems coordinate many facets of animal metabolism, reproduction, and homeostasis, ensuring the proper response to changes in physiology or environment. More recently, hormones have also been shown to govern metazoan aging. Notably, a mild reduction of insulin/IGF1 signaling increases stress resistance and longevity in diverse species across taxa (1). These studies also imply that other hormones impact lifespan. Nuclear hormone receptors are transcription factors that respond to lipophilic hormones such as steroids, fatty acids, and retinoids to regulate gene expression, and are well poised to coordinate global life history traits. Indeed, genetic studies in worms and flies have implicated such molecules in lifespan regulation, but how they do so is not well understood (2-7).DAF-12 is one such nuclear receptor in Caenorhabditis elegans. Homologous to vertebrate vitamin D and LXR receptors (8), DAF-12 controls the choice between reproductive growth and arrest at a long-lived, alternate third larval stage, the dauer diapause, formed under harsh environmental conditions (9). It also specifies third larval temporal fates in the heterochronic pathway (10), a circuit that regulates developmental timing. Finally, DAF-12 and related components modulate organismal lifespan in at least two contexts (2-6): (i) in response to inputs for dauer diapause and (ii) in response to signals from the germ line. Recently, the endogenous ligands of DAF-12 have been discovered to be 3-keto bile acid-like steroids, called ⌬ 4 -and ⌬ 7 -dafachronic acids (11) and related metabolites (12), enabling a direct test of whether these ligands modulate nematode longevity and stress resistance. Here, we specifically examined ⌬ 4 -dafachronic acid. ResultsIn the dauer pathways, environmental cues (temperature, dauer pheromone, food, and cholesterol) are integrated by insulin/ IGF1 and TGF-␤ signaling, which then converge on daf-9/ cytochrome P450 (CYP450...

Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans

“…1). A previous report has shown that DAs are produced in an insulin and TGFb signalling-dependent manner in developing C. elegans under nutrient-favourable conditions 4 . However, we found that DR also induces daf-9 expression in adult mutants lacking functional insulin signalling (daf-16/FOXO mutant) or TGFb signalling (daf-5/SKI and daf-7/TGFb; Supplementary Fig.…”

“…Thus, our observation that DAs are produced in gravid adult worms in response to starvation contrasts with the findings in developing worms. Interestingly, DAs are also produced upon ablation of the germline, an intervention that extends lifespan in both worms and flies [4][5][6] .…”

Caenorhabditis elegans 2007: The premier model for the study of aging

“…The Antebi lab (Gerisch et al, 2007) has been studying endogenous DAF-12 ligands (3-keto bile acid-like steroids), called dafachronic acids. These compounds rescue hormone-deficient mutants, such as daf-9 (cytochrome P450) and daf-36 (Rieske oxygenase), and activate DAF-12.…”

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

“…7,[15][16][17][18][19] Additionally, three members of the nuclear hormone receptor (NHR) family of transcription regulators, DAF-12/FXR, NHR-80/HNF4 and NHR-49/PPARa are important for GSC-less longevity. 7,[20][21][22] Multiple lines of evidence have indicated that these factors link lipid metabolism to reproductive stimuli and aging. DAF-16/FOXO3A, TCER-1/ TCERG1, SKN-1/NRF2 and DAF-12/FXR targets include lipid-metabolic genes, 15,19,20,[23][24][25] PHA-4/ FOXA-and HLH-30/TFEB-mediated enhancement of autophagy contributes to increased lipase activity 17,18 and NHR-80/HNF4 promotes fatty-acid desaturation in long-lived, GSC-less adults.…”

“…7,[20][21][22] Multiple lines of evidence have indicated that these factors link lipid metabolism to reproductive stimuli and aging. DAF-16/FOXO3A, TCER-1/ TCERG1, SKN-1/NRF2 and DAF-12/FXR targets include lipid-metabolic genes, 15,19,20,[23][24][25] PHA-4/ FOXA-and HLH-30/TFEB-mediated enhancement of autophagy contributes to increased lipase activity 17,18 and NHR-80/HNF4 promotes fatty-acid desaturation in long-lived, GSC-less adults. 21 However, the generegulatory network (GRN) in which these factors operate is poorly defined and it remains unclear how their activities allow an animal to not only survive the physiological disruption created by loss of GSCs but to convert it into a beneficial enhancement of health and lifespan.…”