DAF-16/FoxO in Caenorhabditis elegans and Its Role in Metabolic Remodeling

Abstract

DAF-16, the only forkhead box transcription factors class O (FoxO) homolog in Caenorhabditis elegans, integrates signals from upstream pathways to elicit transcriptional changes in many genes involved in aging, development, stress, metabolism, and immunity. The major regulator of DAF-16 activity is the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway, reduction of which leads to lifespan extension in worms, flies, mice, and humans. In C. elegans daf-2 mutants, reduced IIS leads to a heterochronic activation of a dauer survival program during adulthood. This program includes elevated antioxidant defense and a metabolic shift toward accumulation of carbohydrates (i.e., trehalose and glycogen) and triglycerides, and activation of the glyoxylate shunt, which could allow fat-to-carbohydrate conversion. The longevity of daf-2 mutants seems to be partially supported by endogenous trehalose, a nonreducing disaccharide that mammals cannot synthesize, which points toward considerable differences in downstream mechanisms by which IIS regulates aging in distinct groups.

Diagnostic model of combined ceRNA and DNA methylation related genes in esophageal carcinoma

“…In addition, FoxO protein is inactivated by major carcinogenic signals such as phosphatidylinositol-3 kinase pathway and MAP kinase . FoxOs regulate the expression of many genes to control many cell functions, such as cell growth (Niimi et al, 2019), survival (Hassell, 2019), metabolism and antioxidant status (Zečić & Braeckman, 2020). However, recent studies have shown new and unknown functions of FoxO in cancer treatment and promotion, which shows that FOXO factor, has complex roles in the disease.…”

Molecular Effects of Silver Nanoparticles on Monogenean Parasites: Lessons from Caenorhabditis elegans

“…Loss of pqm-1 suppresses DAF-2 activity, which can inactivate daf-16 transcription, probably affecting the resistance of parasites to AgNP exposure as well as accelerated cell death. The decreased expression of pqm-1 is related to aging [ 60 , 133 ]. Likewise, the phospholipase D gene pdl-1 was up-regulated by a 3.51 z-score, and it is also involved in the DAF-16 pathway.…”

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity

“…Activation of oxidative stress responses and proteostasis, as well as modulation of metabolic processes, are also key downstream effects of DAF-16 activation, and the majority of genes within the clusters we identified are also known to be upregulated by DAF-16 (Harris et al, 2020;Honda & Honda, 1999;Li & Zhang, 2016;McElwee, Bubb, & Thomas, 2003;Webb et al, 2016;Zečić & Braeckman, 2020). Significantly upregulated oxidative stress response genes included sodh-1, catalase genes ctl-1 and ctl-3, and members of the cytochrome P450 and glutathione S-transferase families ( Figure 4F), all of which are DAF-16 targets (Webb et al, 2016).…”