F-actin in the Brain Inhibits Autophagy to Promote Neurodegeneration
Researchers here report on an interesting mechanism by which the cell maintenance processes of autophagy are inhibited in the aging brain, in flies at least. Changes in the maintenance of the actin cytoskeleton inside a cell cause this reduction in autophagy, but can be blocked via small molecules in order to restore a more youthful function in brain tissue. In general, approaches to improve autophagy in aging tissue have been shown to produce a slowing of aging and improved function of aged tissues in short-lived species. From what we know of interventions such as exercise and calorie restriction, both of which improve autophagy, the effects on life span are not as large in long-lived species such as our own, even if some of the short term benefits are similar.
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. Actin can be found in two forms: monomeric (G-actin) and filamentous (F-actin). Assembly and disassembly of actin filaments are regulated by a large number of actin-interacting proteins, making maintenance of the actin cytoskeleton highly susceptible to disruption caused by aging. 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.