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 generated a whole-body Armh4-knockout mouse line, and investigated its impact on systemic aging. Under normal feeding conditions, Armh4 deficiency significantly lowered spontaneous mortality and extended maximum lifespan. In the female mice, Armh4 deficiency postponed sexual maturity for one week. At the organ level, the age-related pathologies of the heart, liver, kidney, and spleen were substantially alleviated by Armh4 deletion. Mechanistically, ARMH4 interacted 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 was required for the maintenance of IGF1R/FGFR1 expressions through regulating transcription factor c-Myc. Therefore, ARMH4 maintains a positive-feedback growth signaling to promote aging.