COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells

Area of Science:

• Cellular senescence
• Molecular pathways of cell survival
• Drug discovery for age-related diseases

Background:

• Senolytics selectively eliminate senescent cells, showing promise for cancer, fibrosis, and aging.
• Limited understanding of molecular pathways governing senescent cell survival hinders senolytic drug development.

Purpose of the Study:

• To identify molecular targets essential for senescent cell survival.
• To explore novel therapeutic strategies for senescence-associated diseases.

Main Methods:

• RNA interference (RNAi) screens to identify senescent cell liabilities.
• Genetic and pharmacological inhibition of coatomer complex I (COPI).
• Evaluation of N-myristoyltransferase inhibitors (NMTi) as senolytics.

Main Results:

• COPI vesicle formation was identified as a critical vulnerability in senescent cells.
• Inhibition of COPI led to Golgi dispersal, impaired autophagy, and apoptosis in senescent cells.
• NMT inhibitors mimicked COPI inhibition, demonstrating potent senolytic activity and improving disease outcomes in mouse models.

Conclusions:

• Senescent cells possess a hyperactive secretory apparatus that can be targeted for elimination.
• Inhibiting intracellular trafficking pathways, such as COPI function, represents a viable senolytic strategy.
• NMT inhibitors show potential as senotherapeutics for various senescence-associated conditions, including cancer and non-alcoholic steatohepatitis.