Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell Rep. 2013 Feb 21;3(2):319-27. doi: 10.1016/j.celrep.2013.01.005. Epub 2013 Jan 31.
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.
尽管最近对某些生物中它们的功能存在争议，但人们认为沉默调节蛋白在延长寿命方面发挥着进化上保守的作用。沉默调节蛋白是否可以逆转与衰老相关的退化尚不清楚。组织特异性干细胞在整个生命周期中持续存在，以修复和维持组织，但随着衰老，其自我更新和分化潜能会失调。我们表明，SIRT3 是一种调节线粒体蛋白全局乙酰化景观并减少氧化应激的哺乳动物沉默调节蛋白，它在造血干细胞 (HSC) 中高度富集，在那里它调节应激反应。在年轻的、处于稳态的情况下，SIRT3 对于 HSC 的维持和组织内稳态不是必需的，但在应激或老年时是必需的。重要的是，随着衰老，SIRT3 的表达受到抑制，而在衰老的 HSCs 中上调 SIRT3 可以提高其再生能力。我们的研究阐明了在衰老过程中控制干细胞和组织维持的线粒体动态平衡的可塑性，并表明衰老相关的退化可以通过沉默调节蛋白逆转。
