Oxytocin Enhances Demethylation Through TET Enzyme Expression in Neurons of Aged Mice: Oxytocin as a Potential...

While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (> 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus. Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression. Directly confirming a role for OXTR signaling, TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) null mice, compared with age-matched WT mice. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.