Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge. Academic Article uri icon


  • Circadian disruption aggravates age-related decline and mortality. However, it remains unclear whether circadian enhancement can retard aging in mammals. We previously reported that the small molecule Nobiletin (NOB) activates ROR (retinoid acid receptor-related orphan receptor) nuclear receptors to potentiate circadian oscillation and protect against metabolic dysfunctions. Here we show that NOB significantly improves metabolic fitness in naturally aged mice fed with a regular diet (RD). Furthermore, NOB enhances healthy aging in mice fed with a high-fat diet (HF). In HF skeletal muscle, the NOB-ROR axis broadly activates genes for mitochondrial respiratory chain complexes (MRCs) and fortifies MRC activity and architecture, including Complex II activation and supercomplex formation. These mechanisms coordinately lead to a dichotomous mitochondrial optimization, namely increased ATP production and reduced ROS levels. Together, our study illustrates a focal mechanism by a clock-targeting pharmacological agent to optimize skeletal muscle mitochondrial respiration and promote healthy aging in metabolically stressed mammals.

published proceedings

  • Nat Commun

altmetric score

  • 36.93

author list (cited authors)

  • Nohara, K., Mallampalli, V., Nemkov, T., Wirianto, M., Yang, J., Ye, Y., ... Chen, Z.

citation count

  • 84

complete list of authors

  • Nohara, Kazunari||Mallampalli, Venkata||Nemkov, Travis||Wirianto, Marvin||Yang, Jiah||Ye, Youqiong||Sun, Yuxiang||Han, Leng||Esser, Karyn A||Mileykovskaya, Eugenia||D'Alessandro, Angelo||Green, Carla B||Takahashi, Joseph S||Dowhan, William||Yoo, Seung-Hee||Chen, Zheng

publication date

  • January 2019