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Article Publish Status: FREE
Abstract Title:

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

Abstract Source:

Nat Commun. 2019 Aug 28 ;10(1):3923. Epub 2019 Aug 28. PMID: 31462679

Abstract Author(s):

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

Article Affiliation:

Kazunari Nohara

Abstract:

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.

Study Type : Animal Study

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