Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.
4 affiliations
- 1Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul, South Korea.
- 2Department of Physiology and Medical Science, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon, South Korea.
- 3Department of Physiology, College of Medicine, Soonchunhyang University, Cheonan, South Korea.
- 4Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul, South Korea. [email protected].
Abstract
Neuronal senescence, triggered by oxidative stress and inflammatory responses, is a significant risk factor for brain aging, ultimately leading to cognitive decline. Apelin-13, an exercise-induced myokine, exhibits potential neuroprotective effects by the APJ system, but its protective effects against neuronal senescence and the underlying mechanisms are unknown. This study aimed to elucidate how apelin-13 prevents D-galactose-induced neuronal senescence in SH-SY5Ys, human induced pluripotent stem cell-derived neuronal differentiated cells (iPSC-NDs), and an aging mouse model. The administration of ML233, an apelin receptor APJ agonist, attenuated brain aging and cognitive impairment in D-galactose-induced aging mice. In vitro findings showed that apelin-13 failed to scavenge the excessively generated D-galactose-induced reactive oxygen species (ROS) but prevented aging through APJ-Gαq-mediated signaling in SH-SY5Y cells. Apelin-13 activated protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII) to phosphorylate AMPK, which led to the inhibition of mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 promoted the nuclear translocation of transcription factor EB (TFEB), restoring lysosomal function and autophagic flux impaired by D-galactose. Furthermore, D-galactose treatment increased the expression of GATA binding protein 4 (GATA4), a transcription factor that contributes to paracrine senescence by increasing the expression of pro-inflammatory cytokines. Neuronal autophagy restored by apelin-13 promoted GATA4 clearance, ultimately preventing pro-inflammatory cytokine-induced paracrine senescence under D-galactose conditions. Collectively, these results demonstrate that apelin-13 prevents neuronal senescence by inhibiting the mTORC1-GATA4 axis through the restoration of autophagy. Our study highlights apelin-13 as a promising therapeutic candidate for age-related cognitive decline by targeting the oxidative stress-inflammation-neuronal senescence axis through the modulation of autophagy.
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BibTeX
@article{han2026apelin13,
title = {{Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.}},
author = {Su Jong Han and Ji Hyeon Cho and Jae Ryong Lim and Jee Hyeon Yoon and Ji Yong Park and Han Seung Chang and Su Yeol Kim and Ha Jin Kim and Seung Gyu Lee and Se Jin Mun and Jong Hwa Yun and Chang Woo Chae and Young Hyun Jung and Ho Jae Han},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09121-1},
url = {https://europepmc.org/article/MED/42907440},
note = {CC BY},
}
RIS
TY - JOUR
TI - Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.
AU - Su Jong Han
AU - Ji Hyeon Cho
AU - Jae Ryong Lim
AU - Jee Hyeon Yoon
AU - Ji Yong Park
AU - Han Seung Chang
AU - Su Yeol Kim
AU - Ha Jin Kim
AU - Seung Gyu Lee
AU - Se Jin Mun
AU - Jong Hwa Yun
AU - Chang Woo Chae
AU - Young Hyun Jung
AU - Ho Jae Han
PY - 2026
DA - 2026/07/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09121-1
UR - https://europepmc.org/article/MED/42907440
AB - Neuronal senescence, triggered by oxidative stress and inflammatory responses, is a significant risk factor for brain aging, ultimately leading to cognitive decline. Apelin-13, an exercise-induced myokine, exhibits potential neuroprotective effects by the APJ system, but its protective effects against neuronal senescence and the underlying mechanisms are unknown. This study aimed to elucidate how apelin-13 prevents D-galactose-induced neuronal senescence in SH-SY5Ys, human induced pluripotent stem cell-derived neuronal differentiated cells (iPSC-NDs), and an aging mouse model. The administration of ML233, an apelin receptor APJ agonist, attenuated brain aging and cognitive impairment in D-galactose-induced aging mice. In vitro findings showed that apelin-13 failed to scavenge the excessively generated D-galactose-induced reactive oxygen species (ROS) but prevented aging through APJ-Gαq-mediated signaling in SH-SY5Y cells. Apelin-13 activated protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII) to phosphorylate AMPK, which led to the inhibition of mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 promoted the nuclear translocation of transcription factor EB (TFEB), restoring lysosomal function and autophagic flux impaired by D-galactose. Furthermore, D-galactose treatment increased the expression of GATA binding protein 4 (GATA4), a transcription factor that contributes to paracrine senescence by increasing the expression of pro-inflammatory cytokines. Neuronal autophagy restored by apelin-13 promoted GATA4 clearance, ultimately preventing pro-inflammatory cytokine-induced paracrine senescence under D-galactose conditions. Collectively, these results demonstrate that apelin-13 prevents neuronal senescence by inhibiting the mTORC1-GATA4 axis through the restoration of autophagy. Our study highlights apelin-13 as a promising therapeutic candidate for age-related cognitive decline by targeting the oxidative stress-inflammation-neuronal senescence axis through the modulation of autophagy.
SN - 2041-4889
ER -