Age-related circadian disorganization caused by sympathetic dysfunction in peripheral clock regulation

Abstract

The ability of the circadian clock to adapt to environmental changes is critical for maintaining homeostasis, preventing disease, and limiting the detrimental effects of aging. To date, little is known about age-related changes in the entrainment of peripheral clocks to external cues. We therefore evaluated the ability of the peripheral clocks of the kidney, liver, and submandibular gland to be entrained by external stimuli including light, food, stress, and exercise in young versus aged mice using in vivo bioluminescence monitoring. Despite a decline in locomotor activity, peripheral clocks in aged mice exhibited normal oscillation amplitudes under light–dark, constant darkness, and simulated jet lag conditions, with some abnormal phase alterations. However, age-related impairments were observed in peripheral clock entrainment to stress and exercise stimuli. Conversely, age-related enhancements were observed in peripheral clock entrainment to food stimuli and in the display of food anticipatory behaviors. Finally, we evaluated the hypothesis that deficits in sympathetic input from the central clock located in the suprachiasmatic nucleus of the hypothalamus were in part responsible for age-related differences in the entrainment. Aged animals showed an attenuated entrainment response to noradrenergic stimulation as well as decreased adrenergic receptor mRNA expression in target peripheral organs. Taken together, the present findings indicate that age-related circadian disorganization in entrainment to light, stress, and exercise is due to sympathetic dysfunctions in peripheral organs, while meal timing produces effective entrainment of aged peripheral circadian clocks. Aging decreases day-night fluctuations of physiological functions in our body including sleep-wake cycle. Time-keeping mechanism of our clock is event of “entrainment” to daily environmental cues such as light-dark and food. Shigenobu Shibata from Waseda University in Japan and colleagues investigated a hallmark of age-related change of the circadian clock entrainment system by using non-invasive mouse peripheral clock imaging method. They found that weakened sympathetic regulations in aged animals attenuated internal clock information signaling between central and peripheral clocks, and caused the reduction of light-or exercise/stress-induced clock entrainment, but improved food-induced entrainment. Because circadian clock has an important role for homeostasis, investigating properties of entrainment ability will help us to find good medication strategy for age-related decline of physiological function.