Hyperactive mTORC1/4EBP1 Signaling Dysregulates Proteostasis and Accelerates Cardiac Aging

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Aging Research

Background:

• Mechanistic target of rapamycin complex 1 (mTORC1) signaling is crucial in aging and proteostasis.
• Hyperactivated mTORC1 is linked to aging and age-related diseases, including cardiac dysfunction.
• Rapamycin partially inhibits mTOR signaling, improving cardiac function in aged mice, but downstream pathways remain unclear.

Approach:

• Investigated the role of the mTORC1/4E-binding protein 1 (4EBP1) axis in cardiac aging.
• Utilized a whole-body 4EBP1 knockout (KO) mouse model to mimic a hyperactive 4EBP1/eIF4E axis.
• Assessed cardiac function via echocardiography and analyzed gene expression and protein ubiquitination.

Key Points:

• Young 4EBP1 KO mice showed normal cardiac function, but middle-aged and old KO mice exhibited accelerated cardiac aging with impaired systolic and diastolic function.
• 4EBP1 KO mice displayed significantly increased ribosomal biogenesis and protein ubiquitination compared to wild-type (WT) mice.
• No significant difference in heart failure marker gene expression was observed between 4EBP1 KO and WT mice at advanced ages.

Conclusions:

• A hyperactive 4EBP1/eIF4E axis accelerates cardiac aging.
• Dysregulated proteostasis, indicated by increased ribosomal biogenesis and protein ubiquitination, is a potential mechanism driving accelerated cardiac aging.
• Targeting the mTORC1/4EBP1 pathway may offer therapeutic strategies for age-related cardiac dysfunction.