# ATF5‐Dependent GDF15 Expression Mediates Anesthesia‐Induced Neuroprotection Against Stroke

## TL;DR

This study shows that sevoflurane anesthesia protects against stroke by boosting ATF5 and GDF15, but this protection weakens with age.

## Contribution

The study identifies ATF5 and GDF15 as key mediators of anesthesia-induced neuroprotection and reveals their disruption in aging.

## Key findings

- Sevoflurane preconditioning activates ATF5 and GDF15 to induce mitochondrial stress responses.
- Aging impairs the ATF5–GDF15–UPRmt axis, reducing anesthetic neuroprotection in older brains.
- Targeting mitochondrial function may improve stroke prevention in elderly patients.

## Abstract

Perioperative stroke is a rare but serious complication with a rising incidence in aging populations. Although preclinical studies consistently demonstrate that anesthetics such as sevoflurane can induce neuroprotective preconditioning against ischemic injury, clinical results have remained inconclusive. In this study, it is demonstrated that sevoflurane‐induced neuroprotection is associated with the upregulation of genes involved in the mitochondrial unfolded protein response (UPRmt) and mitochondrial bioenergetic metabolism. The findings emphasize the critical role of ATF5 (activating transcription factor‐5) in mediating these protective effects. Sevoflurane preconditioning markedly increases ATF5 expression and its downstream target GDF15, a key regulator of mitochondrial homeostasis, in the cerebral cortex. However, this protective mechanism is not activated in the aged brain, suggesting that aging impairs the ability to mount a mitochondrial stress response. The results imply a need for age‐specific strategies to reduce perioperative stroke risk, including approaches that target mitochondrial function in elderly patients.

Anesthesia‐induced preconditioning protects against perioperative stroke. By manipulating ATF5 in excitatory neurons, it is shown that anesthesia‐driven ATF5 upregulation activates the mitochondrial unfolded protein response (UPRmt) and elevates GDF15 expression. Aging disrupts this ATF5–GDF15–UPRmt axis, offering a molecular explanation for the diminished efficacy of anesthetic preconditioning in older brains.