Ageing is the main risk factor for human diseases and death. Due to the global ageing, it has been urgent and challenging to understand the molecular basis of this complex biology process. Dietary restriction (DR), reduced food in-take without malnutrition, is one of the most robust environmental interventions that delays ageing. Using model organisms such as C. elegans, previous studies have identified key regulators that mediate the anti-ageing effect of DR. However, it has not been clear whether and how lipid metabolism, a process that is closely related to human health, plays any roles in the response to DR, and whether lipid metabolic enzymes serve as key mediators of DR.
To address these scientific questions, Dr. Di Chen's group carried out a series of research. The results have been recently published in Nature Communications as an article entitled “ACS-20/FATP4 mediates the anti-ageing effect of dietary restriction in C. elegans”.
Dr. Chen's group focused on the acyl-CoA synthetase (ACS) family of enzymes, which play a critical role in the initial stage of fatty acid metabolism. Through an RNAi-based genetic screen, Dr. Chen's group identified ACS-20, the C. elegans ortholog of the fatty acid transporter 4 (FATP4), as a key mediator of DR's protective effect on lifespan and healthspan. Using genomic, genetic, genome editing, molecular and biochemical approaches, Dr. Chen's group demonstrates that the acs-20 mutant functions through the NHR-23 nuclear hormone receptor to regulate transcription of ptr-8, which encodes the Patched receptor ortholog from the Hedgehog pathway. Overexpression of ptr-8 leads to disruption of proteostasis, ER stress, and reduced lifespan and healthspan under DR. This study identifies highly conserved genes as key modulators of ageing in response to nutrients and reveals the underlying transcriptional regulation mechanisms.
ACS-20 mediates the beneficial effect of DR on ageing. Under DR conditions, ACS-20 activates the NHR-23 nuclear receptor to restrict the expression of ptr-8 with an unknown factor. When the acs-20 mutant is subject to DR, NHR-23 fails to bind to the ptr-8 promoter, which leads to ptr-8 overexpression, disruption of proteostasis, ER stress, and reduced lifespan and healthspan.
Zi Wang, a Ph.D. student from Dr. Chen's group, is the first author, and Dr. Di Chen from ZJE is the corresponding author of this paper. Dr. Huanhu Zhu's group from the ShanghaiTech University provided support in lipid analysis. This work was supported by grants from the National Key Research and Development Program of China and National Natural Science Foundation of China (General Projects).
