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

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

doi:10.1038/s41467-019-11926-y

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.

Highlights

Circadian disruption aggravates age-related decline and mortality
Circadian behavioral assays uncovered that NOB led to a twofold increase in distance run/day on voluntary wheels compared with aged regular diet (RD)-fed mice during the active phase (Fig. 1c)
We show that NOB, an ROR agonist compound, strengthens metabolic fitness and physical activity in normally aged mice

Summary

Introduction

Circadian disruption aggravates age-related decline and mortality. it remains unclear whether circadian enhancement can retard aging in mammals. 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. Consistent with the observed energy imbalance where energy expenditure lags behind intake in the elderly, the body mass index increases during aging[2] Such exaggerated adiposity negatively influences organ functions throughout the body including skeletal muscle, the largest, mitochondria-rich metabolic organ with crucial roles in activity, thermogenesis, and overall energy homeostasis. Bmal[1] knockout mice, known to suffer loss of behavioral rhythmicity and defective energy homeostasis, displayed early aging in multiple organs and shortened lifespan[20]

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Conclusion