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ARMH4 accelerates aging by maintaining a positive-feedback growth signaling circuit

Yu Fang1,2, Baosen Wang2,3,4, Qiuxiao Guo1,2

  • 1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Nature Communications
|December 13, 2025
PubMed

Insights

Deleting the ARMH4 gene significantly extends lifespan and delays aging in mice. This research identifies ARMH4 as a key regulator of aging, offering potential anti-aging strategies for a growing elderly population.

Area of Science:

  • Gerontology and aging research
  • Molecular biology and genetics
  • Biochemistry and cellular signaling

Background:

  • Aging is a complex process involving chronological changes across multiple organs.
  • An increasing elderly population highlights the need for effective anti-aging interventions.
  • Previous proteomics studies identified age-related downregulation of ARMH4 in healthy individuals.

Purpose of the Study:

  • To investigate the systemic effects of whole-body Armh4 knockout on aging processes.
  • To determine the impact of Armh4 deficiency on lifespan, mortality, and age-related pathologies.
  • To elucidate the molecular mechanisms by which ARMH4 influences aging.

Main Methods:

  • Generation of a whole-body Armh4-knockout mouse model.
  • Assessment of lifespan, spontaneous mortality, and sexual maturity in knockout mice.
  • Histopathological analysis of major organs (heart, liver, kidney, spleen) to evaluate age-related pathologies.
  • Investigation of molecular pathways, including protein synthesis, autophagy, and signaling cascades (PI3K-Akt-mTORC1, Ras-MEK-ERK).
  • Analysis of protein-protein interactions and gene expression regulation involving ARMH4, IGF1R, FGFR1, and c-Myc.

Main Results:

  • Armh4 deficiency significantly reduced spontaneous mortality and extended maximum lifespan in mice.
  • Female mice lacking Armh4 exhibited a one-week delay in sexual maturity.
  • Age-related pathologies in the heart, liver, kidney, and spleen were substantially alleviated in Armh4-knockout mice.
  • Mechanistically, ARMH4 was found to interact with IGF1R/FGFR1, sensitizing PI3K-Akt-mTORC1 and Ras-MEK-ERK pathways.
  • ARMH4 is essential for maintaining IGF1R/FGFR1 expression via regulation of c-Myc, promoting protein synthesis and inhibiting autophagy.

Conclusions:

  • ARMH4 acts as a positive regulator of aging by promoting growth signaling pathways.
  • Deletion of ARMH4 alleviates age-related organ damage and extends lifespan.
  • Targeting ARMH4 may offer a novel therapeutic strategy for combating age-associated diseases and promoting longevity.

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