F-肌动蛋白的积累会导致大脑衰老并限制健康寿命。

Accumulation of F-actin drives brain aging and limits healthspan in .

作者信息

Schmid Edward T, Schinaman Joseph M, Williams Kylie S, Walker David W

机构信息

Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California 90095, USA.

Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California 90095, USA.

出版信息

Res Sq. 2023 Aug 1:rs.3.rs-3158290. doi: 10.21203/rs.3.rs-3158290/v1.

DOI:10.21203/rs.3.rs-3158290/v1

PMID:37577708

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10418561/

Abstract

The actin cytoskeleton is a key determinant of cell and tissue homeostasis. However, tissue-specific roles for actin dynamics in aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in brains, which is counteracted by prolongevity interventions. Critically, modulating 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.

摘要

肌动蛋白细胞骨架是细胞和组织稳态的关键决定因素。然而，肌动蛋白动力学在衰老（尤其是脑衰老）中的组织特异性作用尚不清楚。在这里，我们表明，大脑中丝状肌动蛋白（F-肌动蛋白）随年龄增长而增加，而延长寿命的干预措施可抵消这种增加。至关重要的是，调节衰老神经元中的F-肌动蛋白水平可预防年龄相关的认知衰退并延长机体健康寿命。从机制上讲，我们表明自噬（神经元稳态所需的一种循环过程）在衰老大脑中肌动蛋白失调时会被破坏。值得注意的是，用细胞骨架药物破坏衰老动物的肌动蛋白聚合可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，降低衰老神经元中的F-肌动蛋白水平可减缓脑衰老，并以自噬依赖的方式促进健康寿命。我们的数据确定过量的肌动蛋白聚合是脑衰老的一个标志，可针对这一标志来逆转脑衰老表型并延长健康寿命。