Advanced paternal age increased metabolic risks in mice offspring.

Area of Science:

• Metabolic Phenotyping
• Epigenetics
• Developmental Biology

Background:

• The Developmental Origins of Health and Disease (DOHaD) theory links early-life conditions to adult chronic diseases.
• Advanced paternal age (APA) is increasingly recognized as a risk factor for offspring health, but the underlying mechanisms require further elucidation.

Purpose of the Study:

• To investigate the metabolic phenotype of offspring from APA fathers.
• To identify inherited alterations in sperm associated with APA and their impact on offspring metabolism.

Main Methods:

• Utilized young father (YF-F0) and old father (OF-F0) C57BL/6J mice models.
• Performed blood glucose testing, lipid analysis, indirect calorimetry, and RNA sequencing on offspring and sperm.

Main Results:

• APA offspring exhibited glucose intolerance, hepatic lipid accumulation, increased adipocytes, and impaired energy balance persisting into old age.
• Significant alterations in lipid metabolism and thermogenesis pathways were observed in offspring livers, with PPAR signaling pathway activation.
• Differentially expressed genes in sperm revealed upregulated pathways related to cholesterol metabolism, type II diabetes mellitus, and endocrine resistance, with notable consistency between father and offspring sperm.

Conclusions:

• Findings support a link between paternal gametes and genomic alterations in progeny.
• Inherited sperm alterations may mediate intergenerational effects of APA on offspring chronic metabolic risks.