The effect of ketogenic diet on aging related gene expression in heart

Aging profoundly remodels the heart through metabolic, inflammatory, and fibrotic processes that increase vulnerability to disease. Dietary interventions such as ketogenic diet (KD) may modulate cardiac metabolism, yet their impact in late life remains unclear, and sex differences are often underexplored. This thesis investigated the transcriptional trajectory of murine cardiac aging under a standard diet (SD), the effects of a late-life KD, and sex-specific responses. Bulk RNA sequencing was performed on hearts from male and female mice at 3, 12, and 24 months on SD, and at 24 months after 12 months on KD. Cardiac aging followed a progressive, stepwise transcriptomic shift, with thousands of genes altered across age groups. Pathway analysis revealed activation of metabolic remodeling, inflammatory signaling, oxidative stress, fibrosis, and hypertrophy. The 12-month KD altered the expression of over 1,000 genes, producing a distinct diet-adapted state rather than reversion to a youthful profile. The key pathways modulated by KD included serotonin, corticotropin-releasing hormone, insulin secretion, and eicosanoid signaling, with upstream regulators such as TGFB1, AGT, PPARA, and glucagon. Sex has emerged as a key factor influencing expression, with both shared and distinct responses to aging. These findings highlight KD as a remodeling but not rejuvenating intervention and underscore the importance of sex-aware approaches in cardiac aging research.