Nuclear hormone receptor NHR-49 is an essential regulator of stress resilience and healthy aging in Caenorhabditis elegans

Abstract

The genome of Caenorhabditis elegans encodes 284 nuclear hormone receptor, which perform diverse functions in development and physiology. One of the best characterized of these is NHR-49, related in sequence and function to mammalian hepatocyte nuclear factor 4α and peroxisome proliferator-activated receptor α. Initially identified as regulator of lipid metabolism, including fatty acid catabolism and desaturation, additional important roles for NHR-49 have since emerged. It is an essential contributor to longevity in several genetic and environmental contexts, and also plays vital roles in the resistance to several stresses and innate immune response to infection with various bacterial pathogens. Here, we review how NHR-49 is integrated into pertinent signaling circuits and how it achieves its diverse functions. We also highlight areas for future investigation including identification of regulatory inputs that drive NHR-49 activity and identification of tissue-specific gene regulatory outputs. We anticipate that future work on this protein will provide information that could be useful for developing strategies to age-associated declines in health and age-related human diseases.

Keywords: GLP-1; HNF4; PPAR; fatty acid desaturation; fatty acid β oxidation; longevity; nhr-49; stress response.

FIGURE 1

Overview of exogenous stressors which activate NHR-49 to promote the activation of stress response genes. Known stressors that influence NHR-49 activity include starvation, oxidative stress, hypoxia, and infection of Caenorhabditis elegans with various pathogens. These stressors are sensed via unknown mechanisms by NHR-49, which in turn upregulates genes involved in stress regulation, such as acs-2 and fmo-2 in the starvation response; sodh-1, skn-1, and fmo-2 in the oxidative stress response; acs-2, fmo-2, and lgg-1 in the hypoxia response; and acs-2 and fmo-2 upon pathogen infection; at least some of these genes then provide resistance to the pertinent stresses. For details see text. Created with BioRender.com.

FIGURE 2

Overview of the signalling pathways that activate NHR-49 to promote lifespan extension. Known upstream signalling pathways and processes that influence NHR-49 activity include long-lived germline-less mutants, dietary restriction, mitochondrial dysfunction, activation of the AMPK/CREB pathway, and low temperature. These conditions induce Caenorhabditis elegans longevity at least in part by activating NHR-49, which promotes the expression of pro-longevity genes (see Figure 3). For details see text. Created with BioRender.com.

FIGURE 3

Overview of processes through which NHR-49 promotes longevity. NHR-49 upregulates genes involved in lipid metabolism and stress response regulation to extend lifespan. To promote stress resistance and enhanced immune response, NHR-49 upregulates genes including fmo-2. NHR-49’s roles in lipid metabolism include the regulation of fatty acid β-oxidation, wherein NHR-49 upregulates acs-2, and fatty acid desaturation, which NHR-49 influences through regulation of fat-5 and fat-7, potentially influencing several linked processes. Collectively, these downstream outputs promote lifespan extension, although not all processes are equally essential in all longevity contexts. Created with BioRender.com.