Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker.

随着年龄的增长，认知能力下降和情绪障碍的频率会增加。许多努力都集中在识别治疗这些疾病的分子和途径上。在这里，我们证明，对老年小鼠全身施用生长分化因子 11 (GDF11) 可以以不依赖神经发生的方式改善记忆并减轻衰老和抑郁样症状。从机制上讲，GDF11 直接作用于海马神经元，通过刺激自噬增强神经元活动。这些神经元的转录组和生化分析表明，GDF11 降低了哺乳动物雷帕霉素靶蛋白 (mTOR)（自噬的主要调节因子）的活性。使用皮质酮诱导的抑郁样表型的小鼠模型，我们还表明 GDF11 可以减弱年轻小鼠的抑郁样行为。对患有重度抑郁症 (MDD) 的年轻人的血清分析显示 GDF11 水平降低。这些发现确定了与 GDF11 在大脑中作用相关的机制途径，并揭示了 GDF11 作为抗抑郁候选药物和生物标志物的未知作用。