Research Paper|Volume 6, Issue 1|pp 48—57

BMAL1-dependent regulation of the mTOR signaling pathway delays aging

Rohini V. Khapre¹, Anna A. Kondratova², Sonal Patel¹, Yuliya Dubrovsky¹, Michelle Wrobel³, Marina P. Antoch⁴, Roman V. Kondratov¹

¹Center for Gene Regulation in Health and Diseases, BGES, Cleveland State University, Cleveland, OH
²Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH
³Tartis Aging, Inc, 640 Ellicott Street, Ste. 444, Buffalo, NY 14203-
⁴Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263

Received: December 24, 2013Accepted: January 28, 2014Published: January 29, 2014

https://doi.org/10.18632/aging.100633

Copyright: © 2014 Khapre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1−/− mice by 50%. Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling. We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.