SIRT3 Reverses Aging-Associated Degeneration

• Published in: Cell reports (Cambridge) Vol. 3; no. 2; pp. 319 - 327
• Main Authors: Brown, Katharine, Xie, Stephanie, Qiu, Xiaolei, Mohrin, Mary, Shin, Jiyung, Liu, Yufei, Zhang, Dan, Scadden, David T., Chen, Danica
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.02.2013; Elsevier
• Subjects: Acetylation; Animals; Cells, Cultured; Cellular Senescence; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Mice; Mice, Knockout; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Oxidative Stress; Reactive Oxygen Species - metabolism; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; Up-Regulation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.01.005

Despite recent controversy about their function in some organisms, sirtuins are thought to play evolutionarily conserved roles in lifespan extension. Whether sirtuins can reverse aging-associated degeneration is unknown. Tissue-specific stem cells persist throughout the entire lifespan to repair and maintain tissues, but their self-renewal and differentiation potential become dysregulated with aging. We show that SIRT3, a mammalian sirtuin that regulates the global acetylation landscape of mitochondrial proteins and reduces oxidative stress, is highly enriched in hematopoietic stem cells (HSCs) where it regulates a stress response. SIRT3 is dispensable for HSC maintenance and tissue homeostasis at a young age under homeostatic conditions but is essential under stress or at an old age. Importantly, SIRT3 is suppressed with aging, and SIRT3 upregulation in aged HSCs improves their regenerative capacity. Our study illuminates the plasticity of mitochondrial homeostasis controlling stem cell and tissue maintenance during the aging process and shows that aging-associated degeneration can be reversed by a sirtuin. [Display omitted] ► SIRT3 is highly enriched in HSCs and suppressed in differentiated hematopoietic cells ► SIRT3 regulates HSC self-renewal under stress or at an old age ► SIRT3 regulates mitochondrial metabolic homeostasis and reduces ROS in HSCs ► SIRT3 is suppressed with age, and its upregulation rejuvenates aged HSCs Despite recent controversy about their function in some organisms, sirtuins are thought to play evolutionarily conserved roles in lifespan extension. It is unclear whether sirtuins can reverse aging-associated degeneration. Here, Scadden, Chen, and colleagues use mouse genetics to show that SIRT3, a mammalian mitochondrial sirtuin, is highly enriched in hematopoietic stem cells (HSCs), where it regulates a stress response. This protective program is suppressed with aging, contributing to compromised HSC function and tissue homeostasis. Furthermore, SIRT3 upregulation improves the functional capacity of aged HSCs and reverses aging-associated degeneration.