| Summary: | Endogenous near 24 h (circadian) rhythms in physiology and behavior are orchestrated by cell autonomous circadian oscillators present in neural and non-neural tissues and the synchronization of these clocks with recurrent environmental time cues is critical for personal well-being, resistance to disease and longevity. As mammals age, the circadian system, from clock gene to cellular activity, begins to break down such that sleep-wake and cardiovascular cycles lose synchronization with the environment, resulting in poor general health and increased susceptibility to cardiovascular diseases. Although converging evidence from previous studies indicate that aging is associated with deficits in the function of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), the mechanisms responsible have not been clearly defined. Therefore, to explore age-related changes, this study entailed in vivo analysis of behavioral (wheel-running) and physiological rhythms (assessment of metabolism and heart rate) and ex vivo assessment of core clock genes in central and peripheral tissues and evaluation of electrophysiological properties of SCN neurons and cardiac myocytes. In current study, aged mice not only showed clear and defined deteriorations in locomotor and metabolic activity, but also displayed disruption in the expression of PER2::LUC within the SCN, arcuate nucleus (Arc), dorsomedial hypothalamus (DMH), paraventricular nucleus (PVN), pituitary gland, heart, lung, liver and adrenal gland. Aging also produced negative effects on the expression of per1 and PER2 at the single cell level in the SCN. In addition, the results gained from visualized sagittal sections revealed that VPAC2 agonist (BAY 55-9837) treated aged tissues (SCN, Arc, DMH and PVN) boosted their circadian properties. Further experiments revealed that in animals where the VPAC2 receptor is absent (Vipr2-/-), there were clear disruptions to all aspects of PER2::LUC expression in the SCN and other circadian oscillators. Another exciting finding was that resveratrol, an activator of mammalian SIRT1 and PGC-1, was able to increase expression of PER2::LUC in SCN, pituitary, and lung of old WT and Vipr2-/- mice. This study also noted that middle-aged SCN per1-expressing neurons have more depolarized resting membrane potential (RMP) and lower firing rate during both day and dusk compared with SCN neurons of very-young and young-adult animals. The middle aged SCN neurons also lack day-dusk variation of RMP and firing activity. One of the most striking findings from the final part of the study was that young mice have a day-night variation in heart rate variability (HRV) whereas older mice do not. This study also reported that while heart rate and HRV were decreased, all other ECG parameters were increased with age during day and night. Moreover, the present study demonstrated cellular hypertrophy, prolongation of action potential duration, increase in peak L-type Ca2+ current and its slower inactivation in aged cardiac myocytes. In general, the results provide further insight into the widespread effects of aging in circadian and cardiac physiology and future studies are necessary to understand the processes that give rise to these changes.
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