Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity

Area of Science:

• Cardiovascular Biology
• Aging Research
• Metabolic Pathways

Background:

• The insulin-like growth factor 1 (IGF1) pathway regulates metabolism and aging, but its role in cardiac aging is debated.
• Inhibition of IGF1 signaling generally extends lifespan, yet its specific effects on the aging heart require clarification.

Purpose of the Study:

• To investigate the lifelong effects of enhanced and reduced insulin-like growth factor 1 receptor (IGF1R) signaling on cardiac health and lifespan in mice.
• To elucidate the molecular mechanisms underlying IGF1R's influence on aging cardiomyocytes.

Main Methods:

• Lifelong study using cardiomyocyte-specific transgenic mouse models with altered IGF1R signaling.
• Assessment of cardiac function via echocardiography and hemodynamics.
• In vitro analyses including histology, mitochondrial respiration, autophagy, and metabolomics.

Main Results:

• Increased IGF1R signaling led to accelerated cardiac aging, heart failure, and reduced lifespan.
• Reduced IGF1R signaling improved cardiac performance during aging and increased lifespan.
• IGF1R activation impaired autophagy and oxidative phosphorylation in aging hearts; reduced IGF1R activity enhanced these processes.

Conclusions:

• Cardiac health and IGF1R signaling exhibit a biphasic relationship, not a linear one.
• Pharmacological inhibition of IGF1R may be beneficial for cardiac aging in older adults, but not in younger individuals.