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Reduced Gbp1 Causes Mitochondrial Dysfunction and Cellular Senescence in Macrophages


We have talked about the polarization of macrophages in a number of previous articles, but, in short, macrophages can have multiple behavioral profiles that determine what roles they play; this is known as polarization. A new study has identified a regulatory protein that controls this process.

Macrophage Polarization

For the purposes of this article, we are interested in the M1 and M2 polarization. The M1 type is pro-inflammatory and aggressive towards invading pathogens, while the M2 type of macrophage is anti-inflammatory in nature, suppressing inflammatory responses and facilitating tissue repair.

Both polarizations have their uses, but in aged people, the balance between M1 and M2 in macrophage populations tends to increasingly favor M1, leading to rising inflammation and inappropriate immune responses.

We need inflammation in the short term, as it is a vital part of the immune response and allows us to effectively combat invading pathogens, but the chronic inflammation associated with aging causes cells to become dysfunctional and tissue maintenance to fail. This is at least in part due to stem cells being inhibited by inflammatory signaling and other sources of persistent inflammation, such as cell debris, senescent cells, and crosslinks.

A new study has identified that the regulatory guanylate binding protein 1 (Gbp1) is linked to the age-related dysfunction of macrophages[1]. The research team shows that the reduction of Gbp1 leads to macrophage dysfunction and a shift to favoring the M1 polarization.


Macrophage polarization is tightly associated with its metabolic reprogramming and immune dysfunction. However, the intracellular molecules/pathways that connect these alterations in inflammatory macrophages remain largely unidentified. Herein, we explored the role of guanylate binding protein 1 (Gbp1), an intracellular antimicrobial protein, in regulating polarization, metabolic reprogramming, and cellular aging of macrophages. We showed that Gbp1 expression in inguinal white adipose tissue is significantly decreased in high-fat diet -fed and aged mice. Gbp1 expression is significantly induced by IFNγ and LPS in macrophages but not adipocytes. Downregulation of Gbp1 expression causes macrophage polarization towards a pro-inflammatory phenotype. Gbp1 knockdown (Kd) macrophages have impaired mitochondrial respiratory function, which is further supported by down-regulation of genes encoding electron transport chain components and genes involved in fatty acid oxidation and mitochondrial function. Moreover, we observed Gbp1 is localized in both cytosol and mitochondrial fraction, and Gbp1 Kd macrophages display decreased mitophagy activity. More interestingly, Gbp1 Kd macrophages undergo senescence as evidenced by increased activation of AMPK-p53 pathway and positive staining of β-galactosidase. These observations suggest that Gbp1 may play an important role in protecting against mitochondrial dysfunction and preserving immune function of macrophages during inflammatory stress and aging.

It is worth noting that while the paper here is focused on obesity as much as aging, the mechanisms are relevant to both.


Understanding and manipulating macrophage polarizations could possibly lead to therapies that combat the chronic inflammation associated with aging.


[1] Qiu, X., Guo, H., Yang, J., Ji, Y., Wu, C. S., & Chen, X. (2018). Down-regulation of guanylate binding protein 1 causes mitochondrial dysfunction and cellular senescence in macrophages. Scientific Reports, 8(1), 1679.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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