title: Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival.
abstract: The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock.
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Guangrui
authors: G
authors: Yang
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Lihong
authors: L
authors: Chen
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Gregory R
authors: GR
authors: Grant
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Georgios
authors: G
authors: Paschos
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Wen-Liang
authors: WL
authors: Song
authors: Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Erik S
authors: ES
authors: Musiek
authors: Department of Ophthalmology, University of Pennsylvania Scheie Eye Institute, Philadelphia, PA 19104, USA.
authors: Vivian
authors: V
authors: Lee
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Sarah C
authors: SC
authors: McLoughlin
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Tilo
authors: T
authors: Grosser
authors: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
authors: George
authors: G
authors: Cotsarelis
authors: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. garret@upenn.edu.
authors: Garret A
authors: GA
authors: FitzGerald
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000375:Aging / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology; D001786:Blood Glucose / Q000378:metabolism; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D059305:Diet, High-Fat; D005124:Eye Abnormalities / Q000473:pathology; D005298:Fertility; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005911:Gliosis / Q000473:pathology; D006197:Hair / Q000254:growth & development; D008136:Longevity; D018345:Mice, Knockout; D010641:Phenotype; D016019:Survival Analysis; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D001786:Blood Glucose