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.
Highlights
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
In the small nematode worm Caenorhabditis elegans, a point mutation in the daf-2 gene is sufficient to double the mean lifespan of the animals by downregulating the Insulin/IGF-1 signaling (IIS) pathway (Kenyon et al 1993; Kimura et al 1997)
Lifespan extension occurs because daf-2 or age-1 mutation leads to the de-phosphorylation and nuclear accumulation of the DAF-16 transcription factor (Kenyon et al 1993; Lin et al 2001; Ogg et al 1997)
Summary
Chromatin Immunoprecipitation (ChIP): Utilizes antibodies specific to the transcription factor of interest (or an associated tag e.g. GFP) to isolate transcription factorChromatin complexes. Any remaining DNA identified either by cloning and sequencing, microarrays, or RNA Seq. DNA Adenine Methyltransferase Identification (DamID): A transcription factor is tagged with a DNA methyl adenosyl transferase that methylates DNA at specific GATC sites within 500 bp of transcription factor binding. Methylated DNA is isolated using the DpnI restriction enzyme and identified using microarrays
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