NR4A1 Acts as a Nutrient Sensor That Inhibits the Effects of Aging

Abstract

Orphan nuclear receptor 4A1 (NR4A1) is a member of the NR4A subfamily that was initially discovered as an intermediate early gene expressed in response to stressors, including inflammatory agents. This review addresses the hypothesis that NR4A1 is a key nutrient sensor that contributes to the anti-aging and health-protective effects of receptor ligands, dietary phenolics, and other diet-derived compounds. There is evidence in animal models including humans that NR4A1 serves as an important gene that decreases the rate of aging and its associated diseases. For example, in humans and mice, NR4A1 expression decreases with age and loss of NR4A1 enhances disease susceptibility, and survival curves show that NR4A1-deficient mice live 4 months less than wild-type animals. An extensive comparison of inflammatory diseases, immune dysfunction, and fibrosis in multiple tissues shows that in NR4A1^-/- mice and rats these diseases and injuries are enhanced compared to wild-type NR4A1^-/- animals. There is evidence showing that structurally diverse NR4A1 ligands reverse the induced adverse effects in NR4A1 wild-type mice. This raises an important question regarding the mechanisms of NR4A1-dependent inhibition of the aging process and the potential for this receptor as a nutrient sensor. It has been well established that polyphenolics, including flavonoids, resveratrol, and other compounds in the diet, are health-protective and decrease the aging process. Recent studies show that resveratrol and flavonoids such as quercetin and kaempferol bind NR4A1 and exhibit protective NR4A1-dependent inhibition of endometriosis and cancer. These limited studies support a role for NR4A1 as a potential dietary sensor of nutrients that are known to be health-protective and a potential nutrient target for improving health.

Keywords: NR4A1; aging; health-protective receptor; polyphenolic target.

Figure 1

NR4A subfamily of NRs. (A) Domain structure of NR4A shows the percentage (%) of similarity between NR4A1, NR4A2, and NR4A3 in 3 domains. (B) Protection interactions of NR4A1 and other ligands with DNA response elements.

Figure 2

Examples of synthetic and natural product-derived chemicals that bind NR4A1 [22,23,24].

Figure 3

Interactions of NR4A1 with various genes/gene products associated with aging.

Figure 4

Proposed model for NR4A1 as a nutrient sensor that plays a constitutive and ligand-induced role in preventing tissue damage. NR4A1 may also contribute to the overall health benefits of dietary polyphenolics.

Figure 5

Health-promoting effects of quercetin in various cell culture and laboratory animal models and their similarity to other synthetic NR4A1 ligands (Table 1).