On March 31, 2022, "Science Advances" entitled "Neuronal C/EBPβ/AEP pathway shortens span via selective GABAnergic neuronal" was published in Science Advances, Chair Professor of Shenzhen Institute of Science and Technology (tentative name, abbreviated as "Shenzhen Polytechnic") Chair Professor of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences degeneration by FOXO repression" article. The latest research results elucidate the core signaling pathway C/EBPβ/AEP that cause neurodegenerative diseases such as Alzheimer's disease, which directly affects the length of life [1].
Alzheimer's disease (AD), commonly known as Alzheimer's disease, is a neurodegenerative disease that gradually worsens over time. Patients present with memory loss, slow movement, and then development of loss of language and mobility, and even death. Alzheimer's disease is more common in the elderly and is generally over the age of 65 years of age, but its true cause is not yet clear.
C/EBPβ plays a role in regulating nutrient metabolism, energy homeostasis, and fat differentiation, and it increases the levels of certain proteins in brain cells; AEP is an enzyme regulated by C/EBPβ. AEP can cut off some proteins, and the gradual aggregation of these fragments can trigger Alzheimer's disease, gradually destroying the patient's memory and thinking ability, and ultimately affecting their ability to perform their daily lives. At the same time, studies have shown that C/EBPβ/AEP activation levels increase with age. Ye Keqiang's team has long been committed to the study of neurodegenerative diseases, based on which they put forward the conjecture that "pathological cognitive decline and lifespan reduction are directly coupled through the C/EBPβ/AEP pathway".
To prove the conjecture, the team used a mouse model to selectively overexpress human C/EBPβ in brain neurons to mimic aging. The typical lifespan of mice is 24-48 months. Transgenic mice carrying one or two copies of C/EBPβ shortened their lifespan to 12-18 months and 5-9 months, respectively. Meanwhile, mice knocked out of a single copy of C/EBPβ gained a longer lifespan than wild-type mice. This suggests that there is a dose effect on lifespan and the C/EBPβ gene. On the other hand, C/EBPβ transgenic mice exhibit abnormal neural activation as well as cognitive impairment, which is a symptom of neurodegenerative diseases. The team found that C/EBPβ directly inhibits the expression of the transcription factor FOXO, thereby specifically inducing apoptosis of GABA neurons. This explains why overexpression of C/EBPβ leads to behavioral phenotypes such as impaired nerve function and epilepsy in mice.
Overexpression of C/EBPβ in mouse nerve cells leads to shortened lifespan and behavioral abnormalities
Next, the team of nematodes (C. elegans) model verified the effect of C/EBPβ on lifespan. C/EBPβ overexpression leads to a reduction in the lifespan of nematodes, and the use of RNAi knockdown of this pathway can prolong the lifespan of nematodes. Only in nerves, not in muscle tissue, overexpression of C/EBPβ can lifespan changes and downregulation of nerve function be observed. This suggests that the pathway's regulation of longevity is based on the effect on nerve function. Knocking out the lgmn-1 (AEP) gene or treating with an AEP inhibitor can eliminate the lifespan effect of C/EBPβ overexpression. This suggests that specific drug formulations should be able to moderately slow down the aging process and prolong human lifespan.
Overexpression of C/EBPβ in nematode nerve cells leads to shortened lifespan with abnormal nerve activation
Ultimately, the team concluded that C/EBPβ, a key transcription factor that affects Alzheimer's disease, also has an impact on longevity. And the pathway is highly conserved from nematodes, mice, and humans.
Interestingly, in this study, manipulated C/EBPβ expression levels were found to respond differently in mice of different sexes. A team study published in Nature earlier in the same month (March 2022) showed that higher follicle-stimulating hormone (FSH) in female mice exacerbated C/EBPβ-dependent protein buildup, cognitive loss and other Alzheimer's symptoms. This further underscores the importance of the C/EBPβ pathway [2].
Ye Keqiang, corresponding author of the paper, said: "Previously, our study found that the C/EBPβ/AEP neural signaling pathway plays a crucial role in driving Alzheimer's disease, and as Alzheimer's disease worsens, the C/EBPβ content gradually increases and the FOXO1 content gradually decreases, this new discovery extends this theory from the pathogenesis of Alzheimer's disease to the regulation of the life cycle." We will further delve into the treatment of Alzheimer's patients with drug inhibition of AEP, delay the aging process, and prolong human lifespan. ”
bibliography
1.Xia, Yiyuan, Hiroshi Qadota, Zhi-Hao Wang, Pai Liu, Xia Liu, Karen X. Ye, Courtney J. Matheny, et al. n.d. ‘Neuronal C/EBPβ/AEP Pathway Shortens Life Span via Selective GABAnergic Neuronal Degeneration by FOXO Repression’. Science Advances 8 (13): eabj8658. https://doi.org/10.1126/sciadv.abj8658.
Written by | Yu Shuang
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