Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation

Area of Science:

• Neuroscience
• Aging Research
• Metabolic Endocrinology

Background:

• Brain aging involves molecular and morphological changes, with inflammation and mitochondrial dysfunction being key factors.
• Adiponectin (APN), an adipokine regulating metabolism, is implicated in aging, but its specific role in brain aging requires further investigation.

Purpose of the Study:

• To investigate the relationship between adiponectin (APN) deficiency and brain aging.
• To explore the underlying mechanisms involving neuroinflammation, mitochondrial function, and HDAC1 signaling.

Main Methods:

• Analysis of APN levels in aged human subjects.
• Assessment of cognitive function, behavior, neuroinflammation, and immunosenescence in APN knockout (KO) mice.
• In vitro studies using primary microglia and BV2 cells.
• Pharmacological interventions with APN receptor agonists and HDAC1 antagonists.

Main Results:

• Declining APN levels correlated with dysregulated cytokines in aged humans.
• APN KO mice showed accelerated brain aging, learning/memory deficits, anxiety, neuroinflammation, and immunosenescence.
• APN deficiency aggravated mitochondrial dysfunction and HDAC1 upregulation.
• AdipoRon and Compound 60 (HDAC1 antagonist) ameliorated mitochondrial deficits and aging markers in cellular and animal models.

Conclusions:

• Adiponectin (APN) plays a critical role in regulating brain aging.
• APN prevents age-related neuroinflammation and mitochondrial impairment.
• HDAC1 signaling is a key mediator in APN's protective effects against brain aging.