Endogenous DAF-16 spatiotemporal activity quantitatively predicts lifespan extension induced by dietary restriction

Abstract

In many organisms, dietary restriction (DR) leads to lifespan extension through the activation of cell protection and pro-longevity gene expression programs. In the nematode C. elegans, the DAF-16 transcription factor is a key aging regulator that governs the Insulin/IGF-1 signaling pathway and undergoes translocation from the cytoplasm to the nucleus of cells when animals are exposed to food limitation. However, how large is the influence of DR on DAF-16 activity, and its subsequent impact on lifespan has not been quantitatively determined. In this work, we assess the endogenous activity of DAF-16 under various DR regimes by coupling CRISPR/Cas9-enabled fluorescent tagging of DAF-16 with quantitative image analysis and machine learning. Our results indicate that DR regimes induce strong endogenous DAF-16 activity, although DAF-16 is less responsive in aged individuals. DAF-16 activity is in turn a robust predictor of mean lifespan in C. elegans, accounting for 78% of its variability under DR. Analysis of tissue-specific expression aided by a machine learning tissue classifier reveals that, under DR, the largest contribution to DAF-16 nuclear intensity originates from the intestine and neurons. DR also drives DAF-16 activity in unexpected locations such as the germline and intestinal nucleoli.

Untargeted metabolomics-based network pharmacology reveals fermented brown rice towards anti-obesity efficacy

“…In addition, in C. elegans , Daf-16 is a key gene transcription factor that controls the insulin/IGF-1 regulatory system and promotes survival. Daf-16 is a gene primarily responsible for lifespan expansion, while it might also have an impact on fat accumulation in C. elegans 18 . Furthermore, hosl-1 specifies the C. elegans homolog of hormone-sensitive lipase 42 , which triggers the primary rate-limiting process in triglyceride breakdown (Supplementary Fig.…”

“…Dietary restriction (DR) extends the lifespan of several animals. DAF-16 modulates the insulin/IGF-1 signaling pathway in C. elegans , promoting lifespan 18 . In C. elegans , several SFAs, MUFAs, and PUFAs, including ω-6 AA (20:4ω-6), ω-3 EPA (20:5ω-3), and monomethyl branched-chain fatty acids, are present, as in humans 19 .…”

Caenorhabditis elegans as a Screening Model for Probiotics with Properties against Metabolic Syndrome

“…In this case, the reported lipid-reducing effect would not be attributed to anti-lipogenic or lipolytic activity but rather to lower energy consumption. C. elegans has been widely used as a model to investigate the effects of calorie restriction, which promotes the extension of nematode lifespan, accompanied by an improvement in stress response and a reduction in the C. elegans fat accumulation mediated by the IIS pathway [64]. For this reason, the replacement of the standard food source by new bacterial strains should be investigated with caution, especially when attributing specific metabolic properties to the probiotics.…”

An Update on Nucleolar Stress: The Transcriptional Control of Autophagy

“…Moreover, forkhead transcription factors, such as DAF-16/FOXO and PHA-4/FOXA, regulate the process of autophagy and have been linked to longevity, as demonstrated in C. elegans [ 60 ]. Interestingly, high DAF-16 activity was found in intestinal nucleoli, in line with the involvement of nucleolar function in lifespan extension [ 61 ]. Accordingly nucleolar size and autophagy play a key role in the process of aging.…”