PAS kinase deficiency reduces aging effects in mice.

Area of Science:

• Gerontology
• Molecular Biology
• Metabolic Research

Background:

• Aging is associated with impaired mitochondrial function, increased oxidative stress, and metabolic dysregulation.
• Nutrient-sensing pathways, including PAS Domain Kinase (PASK), regulate cellular homeostasis and are implicated in aging.
• PASK is a known regulator of hepatic metabolic balance and mitochondrial homeostasis.

Purpose of the Study:

• To investigate the role of PASK in hepatic oxidative stress and metabolic function during aging.
• To analyze the impact of PASK deficiency on mitochondrial function, glucose tolerance, and insulin resistance in aged mice.

Main Methods:

• Analysis of mitochondrial function, oxidative stress markers (ROS/RNS), and key metabolic regulators (PGC1a, SIRT1, NRF2, GCLm, HO1, CS activity) in aged PASK-deficient and wild-type mice.
• Assessment of glucose tolerance, insulin sensitivity (HOMA-IR), and lipid parameters.
• Evaluation of longevity gene (FoxO3a) and cell repair marker (PCNA) expression.

Main Results:

• Hepatic PASK mRNA levels decreased with age.
• Aged PASK-deficient mice exhibited reduced oxidative stress (ROS/RNS) compared to aged WT mice.
• PASK deficiency preserved NRF2, GCLm, HO1, and CS activity, alongside FoxO3a and PCNA expression, suggesting enhanced antioxidant defense and cellular repair.
• PASK-deficient mice demonstrated improved insulin sensitivity and normal glucose tolerance.

Conclusions:

• PASK deficiency confers protection against age-related hepatic oxidative stress and metabolic decline.
• PASK plays a significant role in regulating metabolic homeostasis and mitigating oxidative damage during aging.
• Targeting PASK may represent a novel therapeutic strategy for reducing age-associated damage and improving metabolic health.