Cholesterol biosynthetic pathway induces cellular senescence through ERRα.

Area of Science:

• Cellular and Molecular Biology
• Metabolism and Aging
• Pathology

Background:

• Cellular senescence, a state of stable cell cycle arrest, is linked to aging and age-related diseases.
• Senescent cells exhibit a senescence-associated secretory phenotype, impacting tissue function and healthspan.
• Intracellular metabolic dysregulation is observed in senescence, but its regulatory role remains unclear.

Purpose of the Study:

• To investigate the role of the mevalonate pathway in regulating cellular senescence.
• To elucidate the molecular mechanisms linking mevalonate pathway activity to senescence.
• To determine the contribution of cholesterol biosynthesis to senescence-associated pathologies.

Main Methods:

• Investigated the mevalonate pathway in normal human cells.
• Analyzed downstream effects on cholesterol biosynthesis and ERRα transcriptional activity.
• Utilized ERRα knockout mice to assess in vivo relevance in a high-fat diet model.

Main Results:

• The mevalonate pathway acts as a positive regulator of cellular senescence.
• Cholesterol biosynthesis downstream of the mevalonate pathway mediates senescence induction.
• ERRα activation by this pathway leads to mitochondrial dysfunction, ROS production, DNA damage, and p53-dependent senescence.
• High-fat diet-induced liver senescence is prevented in ERRα knockout mice.

Conclusions:

• Cholesterol biosynthesis and levels are key inducers of cellular senescence.
• The mevalonate pathway promotes an ERRα-dependent mitochondrial program contributing to senescence.
• This mechanism links metabolic homeostasis to cellular senescence and age-related pathological alterations.