(OR14-01-25) Deletion of Cannabinoid 1 Receptor Promotes Healthy Aging by Reducing Hepatic Steatosis in Aged Mice

Objectives: Aging is a progressive biological process that can disrupt the endocannabinoid system (ECS), partly due to increased expression of cannabinoid 1 receptor (CB1R), a key regulatory component of the ECS. CB1R has been implicated in the development of metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to investigate the role of CB1R in age-related phenotype changes, particularly hepatic steatosis, using genetically modified mice with global or liver-specific deletion of CB1R.

Methods: For this study, we generated whole-body CB1R-knockout (CB1KO) and liver-specific CB1R-knockout (LCB1KO) mouse models to evaluate the long-term effects of CB1R deletion on healthy aging. Cross-sectional analyses were conducted on mice aged 3, 6, 12, 18, and 24 months, and their wild-type (WT) counterparts. Key aging and metabolic markers were assessed, including body weight, body composition, serum biomarkers (insulin and leptin levels), and hepatic fat accumulation, which was evaluated through histological analyses using H&E and Oil red O stainings.

Results: Global CB1R deletion resulted in significantly lower body weights throughout aging compared to WT mice, with LCB1KO mice showing significantly reduced body weights from 12 months onward  (p < 0.05). Fat and lean mass were reduced in 18-month-old CB1KO mice compared to age-matched WT controls. Serum insulin levels were significantly lower in CB1KO mice at 18 months (p < 0.01), while plasma leptin levels were markedly reduced in both CB1KO and LCB1KO mice (p < 0.005). Histological analyses revealed that both CB1KO and LCB1KO mice exhibited reduced hepatic fat accumulation and ameliorated age-driven hepatic steatosis (p < 0.001).

Conclusions: Our findings suggest that CB1R deletion improves MASLD, highlighting its potential role in the prevention and treatment of MASLD and other age-associated metabolic disorders.

Funding Sources: This study was supported by the National Institute on Aging (NIA) Intramural Research Program and the Oklahoma Center for Advancement of Science and Technology (OCAST).