Suppressors, receptors and effects of cytokines on the aging mouse biological clock.

During aging, levels of inflammatory cytokines increase and circadian rhythms are frequently altered. We here investigated neurobiological correlates of neuroinflammation and its age-related variation in the hypothalamic suprachiasmatic nucleus (SCN), the master circadian pacemaker. Day/night variations of transcripts encoding cytokine receptors and suppressors of cytokine signaling (SOCS) were correlated in groups of mice of different ages with Fos induction elicited by intracerebroventricular injections of tumor necrosis factor-alpha and interferon-gamma. Cytokine-elicited Fos induction was high at early night, when SOCS1 and SOCS3 levels were low. Such Fos induction was significantly reduced in the older SCN at early night, and paralleled by reduced expression of interferon-gamma receptor transcripts as compared to the younger SCN. In addition, Fos induction at early night exhibited marked sub-regional differences in the SCN between the age groups. The study shows that SOCS1 and SOCS3 are expressed in the biological clock with a day/night variation that may regulate SCN responsiveness to cytokine exposure, and indicates that effects of pro-inflammatory cytokines on the SCN are markedly altered during senescence.