Data-driven transcriptomics analysis identifies PCSK9 as a novel key regulator in liver aging.

Area of Science:

• Gerontology and Hepatology
• Molecular Biology
• Systems Biology

Background:

• The aging process induces significant pathological changes in the liver, impacting overall health.
• Understanding these age-related liver alterations is crucial for developing targeted interventions.

Purpose of the Study:

• To systematically investigate the effects of aging on liver function using a multi-omics approach.
• To identify key genes and pathways involved in liver aging.
• To validate findings in both rat models and human aging studies.

Main Methods:

• Utilized a National Institute of Aging rat aging model (Fischer 344 rats, young vs. aging).
• Employed systems biology approaches, including genome-wide transcriptomics, biochemical assays, histology, and immunohistochemistry.
• Performed co-expression network analysis and validated findings with human aging datasets and single-cell RNA-sequencing.

Main Results:

• Identified widespread pathological changes in aging livers: mitochondrial dysfunction, oxidative stress, decreased NAD+ levels, impaired synthesis, inflammation, lipid metabolism disruption, apoptosis, senescence, and fibrosis.
• Discovered novel driver genes for liver aging through co-expression network analysis.
• Validated proprotein convertase subtilisin/kexin type 9 (PCSK9) as a liver-specific gene implicated in aging.

Conclusions:

• Aging profoundly impacts liver biology through multiple interconnected pathways.
• PCSK9 is identified as a potential therapeutic target for mitigating age-related liver pathology.
• This research opens avenues for interventions to enhance liver health during aging.