The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans

Abstract

In mammals, insulin signalling regulates glucose transport together with the expression and activity of various metabolic enzymes. In the nematode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity. Wild-type animals enter the developmentally arrested dauer stage in response to high levels of a secreted pheromone, accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homologue of the mammalian insulin receptor) and AGE-1 (a homologue of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest development at the dauer stage. Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity. Here we show that null mutations in daf-16 suppress the effects of mutations in daf-2 or age-1; lack of daf-16 bypasses the need for this insulin receptor-like signalling pathway. The principal role of DAF-2/AGE-1 signalling is thus to antagonize DAF-16. daf-16 is widely expressed and encodes three members of the Fork head family of transcription factors. The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes. The probable human orthologues of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-beta effectors in mediating metabolic regulation. These genes may be dysregulated in diabetes.

Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin‐like signaling pathway

“…In our hands, the sgk‐1 mutants had a shortened lifespan (15.5 days mean lifespan, 25 days maximum lifespan, p  = .005). The life‐extending effect of mutating the IIS pathway is dependent on the DAF‐16/FOXO transcription factor remaining outside the nucleus (Gottlieb & Ruvkun, 1994; Kenyon et al., 1993; Murakami & Johnson, 1996; Ogg et al., 1997; Vowels & Thomas, 1992). Reducing daf‐16 expression shortens lifespan in worms (Larsen, Albert, & Riddle, 1995; Ogg et al., 1997).…”

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…Mutations in DAF‐2 (dauer larvae formation‐2), a hormone receptor similar to insulin and IGF‐1 receptors, doubled the lifespan of the worm (Kenyon et al ., 1993; Kimura et al ., 1997). This lifespan extension caused by DAF‐2 mutations required the activity of DAF‐16, which encodes the single FoxO homolog in C. elegans (Kenyon et al ., 1993; Lin et al ., 1997; Ogg et al ., 1997). DAF‐16 is inactivated via its nuclear export by the evolutionary conserved signaling pathway downstream of DAF‐2 receptor (Henderson & Johnson, 2001; Lee et al ., 2001; Lin et al ., 2001).…”

The African turquoise killifish: A research organism to study vertebrate aging and diapause

“…Since the discovery and characterization of the first long‐lived mutants in Caenorhabditis elegans and Saccharomyces cerevisiae more than two decades ago (Kaeberlein, McVey & Guarente, 1999; Kenyon, Chang, Gensch, Rudner & Tabtiang, 1993; Morris, Tissenbaum & Ruvkun, 1996; Ogg et al., 1997; Wang et al., 1993), the concept that aging is a malleable biological process has been well embraced (Finch & Ruvkun, 2001; Gems & Partridge, 2013; Kennedy, 2008; Kenyon, 2005, 2010). …”