ARMH4 accelerates aging by maintaining a positive-feedback growth signaling circuit
Aging is an inevitable process integrating chronological alterations of multiple organs. A growing aging population necessitates feasible anti-aging strategies to deal with age-associated health problems. We previously performed a proteomics analysis in a healthy-aging cohort, and revealed an age-related downregulation of ARMH4. Here we generate a whole-body Armh4-knockout mouse line, and investigate its impact on systemic aging. Under normal feeding conditions, Armh4 deficiency significantly lowers spontaneous mortality and extends maximum lifespan. In the female mice, Armh4 deficiency postpones sexual maturity for one week. At the organ level, the age-related pathologies of the heart, liver, kidney, and spleen are substantially alleviated by Armh4 deletion. Mechanistically, ARMH4 interacts with IGF1R/FGFR1 to sensitize the activation of PI3K-Akt-mTORC1 and Ras-MEK-ERK pathways, consequently promoting protein synthesis and inhibiting autophagy. Moreover, ARMH4 is required for the maintenance of IGF1R/FGFR1 expressions through regulating the transcription factor c-Myc. Therefore, ARMH4 maintains a positive-feedback growth signaling to promote aging.
Authors
- Qiuxiao Guo
- Wang Zh (ORCID: https://orcid.org/0000-0002-1800-2384)
- Baosen Wang (ORCID: https://orcid.org/0000-0002-3629-2477)
- Anqi Xu (ORCID: https://orcid.org/0000-0002-7073-171X)
- Yu Bai (ORCID: https://orcid.org/0000-0002-0371-8590)
- Hui Feng Tan (ORCID: https://orcid.org/0000-0001-7259-2648)
- Hong Li (ORCID: https://orcid.org/0009-0001-3542-0756)
- Junmei Wang (ORCID: https://orcid.org/0000-0002-9607-8229)
- Jiajie Li (ORCID: https://orcid.org/0009-0005-6997-2304)
- Jian Lv (ORCID: https://orcid.org/0000-0002-0315-7084)
- Ningning Guo (ORCID: https://orcid.org/0000-0003-3627-2190)
- Yu Fang (ORCID: https://orcid.org/0000-0002-0287-5279)
- Xiao Ma (ORCID: https://orcid.org/0009-0000-3912-5351)
Institutions
- Guangzhou University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Shenzhen Children's Hospital (CN)
- Fu Wai Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-14
- DOI
- https://doi.org/10.1038/s41467-025-67505-x
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Chinese Academy of Medical Sciences
- Science, Technology and Innovation Commission of Shenzhen Municipality