PRIORITY RESEARCH PAPER

AGING, Vol 1, No 12 , pp 979-987
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Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1

Roman V. Kondratov1, Olena Vykhovanets2,5, Anna A. Kondratova3, and Marina P. Antoch4
1 Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
2 Departments of Cancer Biology Cleveland Clinic Foundation, Cleveland, OH 44195, USA
3 Departments of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
4 Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
5 Present address: Department of Urology, Case Western Reserve University, Cleveland, OH 44106, USA
Running title:
Antioxidant ameliorates premature aging
Key words:
aging, oxidative stress, circadian clock, BMAL1
Received:
12/20/09; accepted: 12/29/09; published on line: 12/30/09
Correspondence:
E-mail:

Abstract

Deficiency of the circadian clock protein BMAL1 leads to premature aging and increased levels of reactivate oxygen species in several tissues of mice. In order to investigate the role of oxidative stress in accelerated aging and development of age-related pathologies, we continuously administered the antioxidant N-acetyl-L-cysteine toBmal1-deficient mice through their entire lifespan by supplementing drinking water. We found that the life long treatment with antioxidant significantly increased average and maximal lifespan and reduced the rate of age-dependent weight loss and development of cataracts. At the same time, it had no effect on time of onset and severity of other age-related pathologies characteristic of Bmal1-/- mice, such as joint ossification, reduced hair regrowth and sarcopenia. We conclude that chronic oxidative stress affects longevity and contributes to the development of at least some age-associated pathology, although ROS-independent mechanisms may also play a role. Our bioinformatics analysis identified the presence of a conservative E box element in the promoter regions of several genes encoding major antioxidant enzymes. We speculate that BMAL1 controls antioxidant defense by regulating the expression of major antioxidant enzymes.