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other·neurology, biomedical research, preclinical research, geriatrics·PMC10656444

GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21

Nature Communications · 31 authors, 13 centres

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TL;DR

This preclinical study used conditional knockout mice to show that deleting the gene GDF11 specifically in excitatory neurons causes cellular senescence, brain ageing, cognitive decline, and shortened lifespan. The mechanism involves GDF11 repressing the pro-senescence factor p21 via the Smad2 pathway.

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The study investigated the role of Growth Differentiation Factor 11 (GDF11) in excitatory neuronal senescence and brain ageing using conditional knockout (cKO) mice (GDF11f/f; CaMKIIα-Cre) and Neuro-2a cells. Researchers found GDF11 is predominantly expressed in post-mitotic excitatory neurons across species. Selective deletion of GDF11 in mouse excitatory neurons induced senescence markers (SA-β-Gal+ cells), neuronal hyperexcitability, dendritic pruning, impaired synaptic input, and cognitive deficits in object recognition and social cognition, while not affecting locomotion or anxiety. Mechanistically, GDF11 deletion upregulated p21 via Smad2 phosphorylation and nuclear translocation, with p21 being necessary for the senescence phenotype. Limitations include the focus on specific brain regions (insular, piriform, and cingulate cortices) and the use of in vitro models alongside in vivo mouse studies. The findings suggest endogenous GDF11 acts as a brake on neuronal senescence and brain ageing through the Smad2-p21 pathway, identifying a potential target for intervention.

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neurology

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ORIGINAL PAPER

PMC10656444

GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21

Nature Communications

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ABSTRACT

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

CITATION EXPORT

Di-Xian Wang, Zhao-Jun Dong, Sui-Xin Deng et al.. GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21. Nature Communications. (2023). https://doi.org/10.1038/s41467-023-43292-1

AUTHORS

31 · 13 CENTRES

Di-Xian Wang, Zhao-Jun Dong, Sui-Xin Deng, Ying-Ming Tian, Yu-Jie Xiao, Xinran Li, Xiao-Ru Ma, Liang Li, Pengxiao Li, Hui-Zhong Chang, Longqi Liu, Fan Wang, Yang Wu, Xiang Gao, Shuang-Shuang Zheng, Hui-Min Gu, Ya-Nan Zhang, Jian-Bin Wu, Fan Wu, Yonglin Peng, Xiao-Wen Zhang, Ren-Ya Zhan, Li-Xia Gao, Qiming Sun, Xing Guo, Xiao-Dong Zhao, Jian-Hong Luo, Ruhong Zhou, Lei Han, Yousheng Shu, Jing-Wei Zhao

1https://ror.org/00ka6rp58grid.415999.90000 0004 1798 9361Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, 310058 Hangzhou, Zhejiang China
2https://ror.org/00a2xv884grid.13402.340000 0004 1759 700XCenter of Cryo-Electron Microscopy, Zhejiang University, 310058 Hangzhou, Zhejiang China
3https://ror.org/013q1eq08grid.8547.e0000 0001 0125 2443Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, 201508 Shanghai, China
4https://ror.org/05gsxrt27BGI Research, 310030 Hangzhou, China
5https://ror.org/00a2xv884grid.13402.340000 0004 1759 700XThe Global Scientific and Technological Innovation Center and the MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, 310058 Hangzhou, Zhejiang China
6https://ror.org/0220qvk04grid.16821.3c0000 0004 0368 8293Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai; Center for Systems Biomedicine, Shanghai Jiao Tong University, 200240 Shanghai, China
7https://ror.org/00a2xv884grid.13402.340000 0004 1759 700XZhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
8https://ror.org/05m1p5x56grid.452661.20000 0004 1803 6319Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, 310003 Hangzhou, China
9grid.13402.340000 0004 1759 700XDepartment of Neurology of the Second Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, 310020 Hangzhou, China
10https://ror.org/059cjpv64grid.412465.0Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
11grid.13402.340000 0004 1759 700XDepartment of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 310058 Hangzhou, Zhejiang China
12https://ror.org/00a2xv884grid.13402.340000 0004 1759 700XNHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
13https://ror.org/00a2xv884grid.13402.340000 0004 1759 700XInstitute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou, China