Role of sirtuin4 in the onset of ageing in gonadotropin-releasing hormone neurons

Abstract

Sexual dysfunction and cognitive deficits are markers of the ageing process. Mammalian sirtuins (SIRT), encoded by sirt 1-7 genes, are sensitive to serotonin (5-hydroxytryptamine, 5-HT). In addition to reproductive function, SIRT and 5-HT regulate cognitive functions. The selective serotonin reuptake inhibitor; citalopram (CIT), a potent antidepressant, causes sexual dysfunction as a side effect in rodents and humans. Hence, we studied sirt mRNA expression (RT-PCR) and protein (immunohistochemistry) in the preoptic area (POA) of male mice after chronic CIT treatment (10mg/kg for 4 wk) and during ageing. SIRT4 immunoreactivity was observed mainly in neurons in the POA. sirt1, sirt4, sirt5, and sirt7 were up-regulated in the ageing POA of 52 wk (mid-age) aged male mice. The number of SIRT4 immunoraective neurons increased in the medial septum area (12 wk 1.00±0.15 vs 36 wk 1.68±0.14 vs 52 wk 1.54±0.11, p<0.05) of 52 wk old mice. Furthermore we observed that CIT treatment up-regulated sirt2 and sirt4 expression in comparison to 12 weeks (wk) old male mice. sirt could mediate ageing processes in the POA which includes deficits in social recognition and reproductive dysfunction. The up-regulation of SIRT4 immunoreactive cells only by ageing and not by CIT points to additional factors other than 5-HT might be important for the modulation of SIRT4. Together, these studies suggest that 5-HT and ageing might utilize SIRT4 in the POA as a common pathway to regulate reproduction amongst other functions.