Quercetin, caffeic acid and resveratrol regulate circadian clock genes and aging-related genes in young and old human lung fibroblast cells

Mol Biol Rep. 2020 Feb;47(2):1021-1032. doi: 10.1007/s11033-019-05194-8. Epub 2019 Nov 26.


The circadian timing system of mammals is synchronized in concert with a central clock, but is also influenced by additional stimuli, including nutrients. However, little research has been done on polyphenols other than resveratrol and there seem to be no studies on their influence on young and old cells. The purpose of this study was to analyse the potential effects of quercetin, caffeic acid, and resveratrol on young and old fibroblast cells in the expressions of different clock genes and aging-related genes, and further investigate the mechanism. The mRNA expression of different clock genes and aging-related genes was assessed by quantitative real-time PCR. The protein levels of clock genes (BMAL1, PER1 and SIRT1) and glucocorticoid receptor α (GRα) were assessed by ELISA. Quercetin and caffeic acid in old fibroblast cells showed higher clock gene expression than resveratrol, quercetin increased Sirt1 expression, and caffeic acid increased Sirt6 expression indicating the possibility of an anti-aging effect. Also, quercetin and caffeic acid showed higher clock-controlled gene (Sirt1 and NR1D1) expression than resveratrol in young fibroblast cells. It appears that caffeic acid acts on NRF2 expression, and in turn to the actions of GRα, GDF11, Sirt1, and Sirt6. Regarding the increased expression of Per1, the activation effect on NR1D1 was confirmed only for caffeic acid in young fibroblast cells. Our results have confirmed the interplay of the circadian clock genes and cellular aging.

Keywords: Caffeic acid; Circadian clock genes; NR1D1; NRF2; Quercetin; Resveratrol.

MeSH terms

  • ARNTL Transcription Factors / metabolism
  • Age Factors
  • Aging / genetics
  • CLOCK Proteins / genetics*
  • Caffeic Acids / pharmacology
  • Cell Line
  • Circadian Clocks / drug effects*
  • Circadian Clocks / genetics
  • Circadian Rhythm / drug effects*
  • Circadian Rhythm / genetics
  • Fibroblasts / metabolism
  • Humans
  • NF-E2-Related Factor 2 / metabolism
  • Polyphenols / metabolism
  • Quercetin / pharmacology
  • Receptors, Glucocorticoid / metabolism
  • Resveratrol / pharmacology
  • Sirtuin 1 / metabolism


  • ARNTL Transcription Factors
  • Caffeic Acids
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Polyphenols
  • Receptors, Glucocorticoid
  • glucocorticoid receptor alpha
  • Quercetin
  • CLOCK Proteins
  • SIRT1 protein, human
  • Sirtuin 1
  • Resveratrol