Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2010 Nov 24;143(5):813-25. doi: 10.1016/j.cell.2010.10.007.
The progressive loss of muscle strength during aging is a common degenerative event of unclear pathogenesis. Although muscle functional decline precedes age-related changes in other tissues, its contribution to systemic aging is unknown. Here, we show that muscle aging is characterized in Drosophila by the progressive accumulation of protein aggregates that associate with impaired muscle function. The transcription factor FOXO and its target 4E-BP remove damaged proteins at least in part via the autophagy/lysosome system, whereas foxo mutants have dysfunctional proteostasis. Both FOXO and 4E-BP delay muscle functional decay and extend life span. Moreover, FOXO/4E-BP signaling in muscles decreases feeding behavior and the release of insulin from producing cells, which in turn delays the age-related accumulation of protein aggregates in other tissues. These findings reveal an organism-wide regulation of proteostasis in response to muscle aging and a key role of FOXO/4E-BP signaling in the coordination of organismal and tissue aging.
肌肉力量在衰老过程中的逐渐丧失是一种发病机制尚不清楚的常见退行性事件。尽管肌肉功能下降先于其他组织的与年龄相关的变化，但它对全身衰老的贡献尚不清楚。在这里，我们表明在果蝇中，肌肉衰老的特征是蛋白质聚集体的逐渐积累，这些聚集体与肌肉功能障碍有关。转录因子 FOXO 及其靶标 4E-BP 至少部分地通过自噬/溶酶体系统去除受损蛋白，而 foxo 突变体则具有功能失调的蛋白稳态。FOXO 和 4E-BP 都可延迟肌肉功能下降并延长寿命。此外，肌肉中的 FOXO/4E-BP 信号会降低摄食行为和产生细胞释放胰岛素，这反过来又会延迟其他组织中与年龄相关的蛋白质聚集体的积累。这些发现揭示了针对肌肉衰老的蛋白质稳态的全身调节，以及 FOXO/4E-BP 信号在协调机体和组织衰老中的关键作用。
