F- 肌动蛋白的积累导致大脑衰老，并限制果蝇的健康寿命。
Accumulation of F-actin drives brain aging and limits healthspan in Drosophila.
机构信息
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
出版信息
Nat Commun. 2024 Oct 25;15(1):9238. doi: 10.1038/s41467-024-53389-w.
The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions. Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.
肌动蛋白细胞骨架是细胞结构和内稳态的关键决定因素。然而，衰老过程中肌动蛋白动力学的可能组织特异性变化，尤其是大脑衰老，尚不清楚。在这里，我们表明果蝇大脑中的丝状肌动蛋白（F-actin）随着年龄的增长而增加，这一现象可以通过延长寿命的干预来抵消。至关重要的是，降低衰老神经元中的 F-actin 水平可以防止认知能力下降的发生，并延长生物体的健康寿命。从机制上讲，我们表明自噬是神经元内稳态所必需的一种回收过程，在衰老大脑中肌动蛋白失调时会被禁用。值得注意的是，用细胞骨架药物破坏衰老动物中的肌动蛋白聚合可以将大脑自噬恢复到年轻水平，并逆转大脑衰老的细胞特征。最后，减少衰老神经元中的 F-actin 水平以自噬依赖的方式减缓大脑衰老并延长健康寿命。我们的数据表明，肌动蛋白聚合过多是大脑衰老的一个标志，可以作为治疗靶点逆转大脑衰老表型并延长健康寿命。
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