BMAL1-dependent regulation of the mTOR signaling pathway delays aging

Sonal Patel,Michelle Wrobel,Yuliya Dubrovsky,Rohini V Khapre,Marina P Antoch,Anna A Kondratova,Roman V Kondratov

doi:10.18632/aging.100633

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.

Highlights

The Target of Rapamycin (TOR) signaling pathway is a critical regulator of anabolic activities, growth and proliferation of cells [1, 2]
In order to study the mTOR signaling pathway as a potential molecular mechanism of BMAL1-dependent control of aging, we decided to compare activity of mTOR signaling in cells isolated from wild type and BMAL1-deficient mice. mTOR is a serine/threonine protein kinase found in two complexes: mTOR Complex 1 and mTOR Complex 2. mammalian Target of Rapamycin Complex 1 (mTORC1) activity is implicated in regulation of metabolism and aging, while the role of mTORC2 in these processes is considered to be less significant [5], we assayed the activity of mTORC1. mTORC1 phosphorylates a number of downstream targets including ribosomal protein S6 kinase 1 (S6K1) and elongation factor 4E binding proteins (4EBPs) [2, 22,23,24,25]
S6K1 is phosphorylated by mTORC1 on threonine 389 (T389); 4EBP1 is phosphorylated on threonine 37 and 46 (T37/T46)

Summary

INTRODUCTION

The Target of Rapamycin (TOR) signaling pathway is a critical regulator of anabolic activities, growth and proliferation of cells [1, 2]. The circadian clock controls glucose and lipid homeostasis [14], cell redox state regulation [15], cell cycle [16] and genotoxic stress response [17]. All these signaling pathways contribute to the circadian control of metabolism. Both clock-dependent regulation of reactive oxygen species homeostasis [18] and circadian control of the activity of histone deacetylases from the sirtuin family [19, 20] were proposed as potential molecular links between the circadian clock and aging [21]. Using a variety of in vitro and in vivo approaches we show that the circadian and mTOR pathways are connected through the activity of BMAL1 and this connection is important for delay of aging

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES