Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge

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

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


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.

Original languageEnglish (US)
Article number3923
JournalNature communications
Issue number1
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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