The hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, synchronizing peripheral clocks through oscillations in core clock genes and proteins. Circadian disruption contributes to immunosenescence, aging, and neurodegenerative disorders such as Parkinson's disease (PD). Previous work from our group demonstrated age-related changes in circadian rhythms of clock genes, protein levels, and serotonin metabolism in the SCN and substantia nigra (SN) of male Wistar rats. This study examined the age of onset for circadian misalignment in clock (rBmal1, rCry1, rCry2, rPer1, rPer2), immune (rCox2, rIl1β, rIl4, rTgfβ1), and PD-associated (rLrrk2, rPark2, rPark7, rSnca) genes in SCN and SN. Male Wistar rats aged 3 (adult), 12 (middle-aged), and 24 (aged) months were studied. In SCN, rPark2 decreased and rSnca increased in 12 months and 24 months, while rCry1 and rPer2 were elevated in 12 months. Rhythmicity of rTgfβ1 declined in 24 months. In SN, rBmal1 rhythmicity was abolished in 24 months, while rPark2 lost rhythmicity in 12 months and 24 months. rSnca and rIl1β were elevated in 24 months. Misalignments in rCry1, rPer2, rIl4, rIl1β, rTgfβ1, and rLrrk2 in SCN, and rCry2, rIl4, rLrrk2, rPark2, and rSnca in SN appeared by middle age. A ketogenic diet intervention (KDI) resulted in modulation of rhythmic expression of rPer2, rSnca, rCry1, rTgfβ1, and rPark2 in SCN and improved rPark2, rSnca, and rIl1β in SN. These findings indicate that translationally, circadian misalignment in PD-related genes emerges early, suggesting its potential as a biomarker for preclinical PD. Moreover, dietary strategies such as KDI highlight promising non-pharmacological approaches to preserve circadian integrity, delay neurodegeneration, and guide personalized interventions in at-risk individuals.
