Lessons from C. elegans: signaling pathways for longevity

Abstract

Recent research using model organisms such as the nematode Caenorhabditis elegans has highlighted a crucial role for several conserved signaling pathways in longevity determination. Here, we review three major endocrine- and nutrient-sensing signaling pathways with influence on lifespan, the insulin/insulin-like growth factor (IGF), target of rapamycin (TOR), and germline signaling pathways. Although these pathways engage distinct sets of transcription factors, the three pathways appear to modulate aging in C. elegans through partially overlapping effector mechanisms, including lipid metabolism and autophagy. This review highlights the latest advances in our understanding of how the insulin/IGF-1, TOR, and germline signaling pathways utilize different transcription factors to modulate aging in C. elegans with special emphasis on the role of lipid metabolism and autophagy.

Figure 1. Overview of insulin/IGF-1 (A) and TOR (B) signaling in C. elegans aging

A. In daf-2/InR insulin-receptor mutants, insulin-like peptides (e.g., INS-7) secreted from neurons reach intestinal cells and trigger the canonical insulin-signaling pathway, which prevents DAF-16/FOXO from entering the nucleus. Other mechanisms of DAF-16/FOXO regulation include ubiquitination (RLE-1/E3 ligase) and arginine methylation (PMRT-1/methylase). Nuclear-localized DAF-16/FOXO activity is enhanced by the action of SMK-1/SMEK and HSF-1, and is inhibited by HCF-1. The transcription factor SKN-1/Nrf is also required for longevity in daf-2/InR mutants. Collectively, these factors transcriptionally regulate multiple output processes as noted. Autophagy is another cellular process required for daf-2/InR mutants to live long. It is not yet known whether autophagy is a transcriptionally regulated process in daf-2/InR mutants. B. TOR responds to nutrients and functions in two different complexes, TORC1 and TORC2. In analogy with mammalian studies, TORC1 is thought to interact with DAF-15/Raptor as well as Rag GTPases like RAGA-1, RAGC-1, and RHEB-1/Rheb. TORC1 and TORC1 specifically impair the activity of DAF-16/FOXO and SKN-1/Nrf, whereas it is not yet clear which of the two TOR complexes regulates PHA-4/FOXA (indicated by dashes lines). By using these transcription factors, TOR inhibits the expression of at least certain lipolysis-, autophagy-, and detoxification-associated genes. Listed as a cytoplasmic process, TOR signaling also likely modulates aging through a general suppression of translation. While the intestine has been linked to the longevity mediated by TORC1, the specific tissue requirements for TOR-dependent effects on aging have not yet been systematically investigated. Factors with longevity-promoting effects are in green and those with lifespan-limiting effects are in red. Transcription factors are in boxes. See text for details.

Figure 2. Overview of germline signaling in C. elegans aging

Lifespan extension via germline removal, for example by mutation of glp-1/Notch, depends on at least four signaling mechanisms: reduced TOR signaling (likely to regulate autophagy), DAF-16/FOXO regulation, increased steroid signaling via the DAF-36/DAF-9/DAF-12 pathway (which regulates various genes), and increased NHR-80/HNF-4 signaling (which enhances fatty-acid desaturation). Of these mechanisms, the most-studied mechanism is DAF-16/FOXO regulation. Germline-less animals require specific cofactors (not required in daf-2/InR mutants) for activation of DAF-16/FOXO in the nucleus of intestinal cells. DAF-12/FXR, TCER-1/TCERG1, KRI-1/KRIT-1 and PHI-62 all function specifically in germline-less animals, whereas DAF-18/PTEN, SMK-1/SMEK and HSF-1 are common between the insulin/IGF-1 and germline signaling pathways. Cell-nonautonomous regulation of DAF-16/FOXO is also mediated through a microRNA, mir-71, which is produced in neurons. Factors with longevity-promoting effects are in green and those with lifespan-limiting effects are in red. TOR effects are listed in grey to indicate that these links are presently inferred. Transcription factors are in boxes. See text for details.