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Published on: September 9, 2021
Targeting FABP4 in elderly mice rejuvenates liver metabolism and ameliorates aging-associated metabolic disorders
Jian Lv1, Yimeng Hu2, Lili Li3
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen 518057, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Introduction:
Aging is characterized by progressive metabolic dyshomeostasis that increases morbidity and mortality. Solutions for optimizing healthy aging are challenged by lacking appropriate biomarkers. Moreover, druggable targets to rejuvenate the aging-associated metabolic phenotypes remain unavailable.
Methods:
Proteomics analysis was performed in a cohort of young and elderly adults. Circulating levels of insulin-like growth factor 1 (IGF-1) and fatty acid binding protein 4 (FABP4) were evaluated by ELISA. FABP4 was silenced in elderly mice by adeno-associated virus. Metabolic activities were measured by metabolic cages. Cognitive function was evaluated by Morris water maze. Glucose and lipid metabolism were evaluated by biochemistry assays with blood samples. RNA-seq in mouse liver was performed for transcriptome analysis.
Results:
Among 9 aging-sensitive proteins shared by both male and female, FABP4 was identified as a reliable aging biomarker in both human and mouse. Silencing FABP4 in elderly mice significantly rejuvenated the aging-associated decline in metabolic activities. FABP4 knockdown reversed the aging-associated metabolic disorders by promoting degradation of cholesterol and fatty acids, while suppressing gluconeogenesis. Transcriptome analysis revealed a restoration of the pro-aging gene reprogramming towards inflammation and metabolic disorders in the liver after FABP4 knockdown. FABP4 overexpression promoted human LO2 cell senescence. Moreover, administration of an FABP4 inhibitor BMS309403 delivered metabolic benefits in elderly mice.
Conclusion:
Our findings demonstrate FABP4 as a reliable aging biomarker as well as a practicable target to improve healthy aging in the elderly.
Insights
Fatty acid binding protein 4 (FABP4) is identified as a reliable aging biomarker. Targeting FABP4 can rejuvenate metabolic function and improve healthy aging in the elderly.
Area of Science:
- Gerontology
- Metabolic Research
- Biomarker Discovery
Background:
- Aging is associated with metabolic dysregulation, increasing disease risk.
- Effective biomarkers and therapeutic targets for healthy aging are lacking.
- Metabolic phenotypes in aging require rejuvenation strategies.
Purpose of the Study:
- To identify reliable aging biomarkers.
- To investigate FABP4 as a potential therapeutic target for aging.
- To explore FABP4's role in metabolic dyshomeostasis during aging.
Main Methods:
- Proteomics analysis in human cohorts.
- ELISA for circulating IGF-1 and FABP4 levels.
- FABP4 silencing in elderly mice (AAV-mediated).
- Metabolic cage analysis, cognitive tests, and biochemical assays.
- RNA-seq for liver transcriptome analysis.
- FABP4 inhibitor administration (BMS309403).
Main Results:
- FABP4 identified as a conserved aging biomarker in humans and mice.
- FABP4 silencing rejuvenated metabolic activity and reversed aging-associated metabolic disorders.
- FABP4 knockdown promoted lipid/cholesterol degradation and suppressed gluconeogenesis.
- Transcriptome analysis showed restoration of liver gene expression.
- FABP4 inhibition improved metabolic parameters in elderly mice.
Conclusions:
- FABP4 serves as a dependable biomarker for aging.
- Targeting FABP4 offers a practical strategy to enhance healthy aging.
- FABP4 modulation presents a therapeutic avenue for age-related metabolic decline.
