DAF-16 target identification in C. elegans: past, present and future

Abstract

In C. elegans, mutations in the conserved insulin/IGF-1 signaling (IIS) pathway lead to a robust extension in lifespan, improved late life health, and protection from age-related disease. These effects are mediated by the FoxO transcription factor DAF-16 which lies downstream of the IIS kinase cascade. Identifying and functionally testing DAF-16 target genes has been a focal point of ageing research for the last 10 years. Here, I review the recent advances in identifying and understanding IIS/DAF-16 targets. These studies continue to reveal the intricate nature of the IIS/DAF-16 gene regulation network and are helping us to understand the mechanisms that control lifespan. Ageing and age related disease is an area of intense public interest, and the biochemical characterization of the genes involved will be critical for identifying drugs to improve the health of our ageing population.

Vitellogenin-RNAi and ovariectomy each increase lifespan, increase protein storage, and decrease feeding, but are not additive in grasshoppers

“…Both TOR and ILS are involved in lifespan extension (e.g., Johnson et al 2013; Kaletsky and Murphy 2010). These two pathways share transcription factors (e.g., DAF-16/FOXO and HSF-1) and may be important in investing resources from somatic preservation to reproduction (DePina et al 2011; Tullet 2015). …”

Genetics and Pharmacology of Longevity

“…The pro-longevity effects of FOXO overexpression in mammals await experimentation, but genetic variances in the FOXO3A loci are enriched in human centenarians (Barzilai, Huffman, Muzumdar, & Bartke, 2012;Slagboom et al, 2011). Given that FOXO is considered the downstream pro-longevity effector of IIS down-regulation, research is focusing on identifying either a transcriptional signature for healthy life span or the genes that modulate the aging process (Alic, Andrews, et al, 2011;Bai, Kang, Hernandez, & Tatar, 2013;McElwee et al, 2007;Murphy et al, 2003;Schuster et al, 2010;Tullet, 2014). It has been documented that the DAF-16 transcriptional response includes the activation of cellular defense mechanisms, including genes with antioxidant properties like superoxide dismutases and catalases (five and three, respectively in C. elegans), genes encoding for peptides with antipathogenicity effects, detoxification, and heat-shock proteins (Murphy, 2006;Shore & Ruvkun, 2013).…”

“…DAF-16 is known to be required for the life span extension by IIS down-regulation. Thus, efforts to identify the downstream effectors have been a priority in the field (Murphy, 2006;Tullet, 2014). Murphy and colleagues used microarray analysis to identify gene expression changes in several IIS worm mutants, allowing the identification of common transcriptional signatures.…”

The interconnectedness of ageing: does the convoy principal apply?

“…This is supported by the review from Pararasa et al (Pararasa, Bailey et al 2014) describing evidence for the role of adipose tissue and circulating free fatty acids in the increased insulin resistance, cardiovascular disease risk and inflammation in older adults. In a related article describing the mechanisms behind regulation of longevity role by the C. elegans FOXO transcription factor ortholog DAF-16 (Tullet 2014). These articles collectively provide novel insight into the role that energy homeostasis has on ageing and longevity.…”