Date of Award

2014

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Kondratov, Roman

Subject Headings

Circadian rhythms, Cellular signal transduction, Circadian Clock Biological Clock BMAL1 Aging Mice mTOR signaling pathway Feeding Senescence oxidative stress

Abstract

Understanding mechanisms of aging is important for the treatment and prevention of age-associated pathologies. However, these mechanisms are not well understood. Recently we have demonstrated that the circadian clock (an internal time keeping system) regulates longevity in mammals, but the molecular mechanisms are not known. The aim of our current study is to investigate a possible interconnection between the circadian clock and mTORC1 (mammalian target of Rapamycin) signaling pathway. mTORC1 pathway is a nutrient response pathway involved in many cellular processes many recent studies indicate a role of mTORC1 pathway in aging. Here we demonstrate that circadian system regulates mTORC1 signaling in vivo. Analysis of liver, heart and spleen from WT mice reveals circadian rhythms in phosphorylation of known mTOR targets such as S6K1 and 4EBPs. These rhythms are disrupted in the tissues of BMAL1 KO mice providing potential mechanistic explanation of reduced longevity of these mice. Further analysis of expression of mTORC1 complex components and upstream regulators demonstrated that some of them have circadian rhythms at protein and mRNA levels. Taken together, these results suggest that circadian clock controls aging by regulating mTOR signaling pathway through BMAL1 dependent control of gene expression

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