Histone modifications change with age, dietary restriction and rapamycin treatment in mouse brain

Abstract

// Huan Gong 1,5 , Hong Qian 1 , Robin Ertl 2,6 , Clinton M. Astle 2 , Gang G. Wang 3 , David E. Harrison 2 and Xiangru Xu 1,4 1 Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA 2 The Jackson Laboratory, Bar Harbor, ME, USA 3 Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 4 Max Planck Institute for Biology of Ageing, Cologne, Germany 5 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, China 6 Center for Natural and Health Sciences, Marywood University, Scranton, PA, USA Correspondence to: Xiangru Xu, email: // David E. Harrison, email: // Keywords : gerotarget, gerontology, health span, mTOR, rapalogs Received : April 17, 2015 Accepted : April 21, 2015 Published : May 20, 2015 Abstract The risk of developing neurodegenerative disorders such as Alzheimer’s disease (AD) increases dramatically with age. Understanding the underlying mechanisms of brain aging is crucial for developing preventative and/or therapeutic approaches for age-associated neurological diseases. Recently, it has been suggested that epigenetic factors, such as histone modifications, maybe be involved in brain aging and age-related neurodegenerations. In this study, we investigated 14 histone modifications in brains of a cohort of young (3 months), old (22 months), and old age-matched dietary restricted (DR) and rapamycin treated BALB/c mice. Results showed that 7 out of all measured histone markers were changed drastically with age. Intriguingly, histone methylations in brain tissues, including H3K27me3, H3R2me2, H3K79me3 and H4K20me2 tend to disappear with age but can be partially restored by both DR and rapamycin treatment. However, both DR and rapamycin treatment also have a significant impact on several other histone modifications such as H3K27ac, H4K16ac, H4R3me2, and H3K56ac, which do not change as animal ages. This study provides the first evidence that a broad spectrum of histone modifications may be involved in brain aging. Besides, this study suggests that both DR and rapamycin may slow aging process in mouse brain via these underlying epigenetic mechanisms.