Effects of aging on central and peripheral mammalian clocks

Abstract

Circadian organization changes with age, but we do not know the extent to which age-related changes are the result of alterations in the central pacemakers, the peripheral oscillators, or the coupling mechanisms that hold the system together. By using transgenic rats with a luciferase (luc) reporter, we assessed the effects of aging on the rhythm of expression of the Period 1 (Per1) gene in the suprachiasmatic nucleus (SCN) and in peripheral tissues. Young (2 months) and aged (24 -26 months) Per1-luc transgenic rats, entrained to light-dark cycles, were killed, and tissues were removed and cultured. Per1-luc expression was measured from 10 tissues. In the SCN, the central mammalian pacemaker, Per1-luc expression was robustly rhythmic for more than 7 weeks in culture. The only difference between SCN rhythmicity in young and old rats was a small but significant age-related shortening of the free-running period. Circadian rhythmicity in some peripheral tissues was unaffected by aging, whereas rhythmicity in other tissues was either phase advanced relative to the light cycle or absent. Those tissues that were arrhythmic could be induced to oscillate by application of forskolin, suggesting that they retained the capacity to oscillate but were not being appropriately driven in vivo. Overall, the results provide new insights into the effects of aging on the mammalian circadian system. Aging seems to affect rhythms in some but not in all tissues and may act primarily on interactions among circadian oscillators, perhaps attenuating the ability of the SCN to drive damped oscillators in the periphery.T he SCN is a circadian pacemaker structure that drives myriad behavioral and physiological rhythms in mammals (1). Surgical destruction of the SCN abolishes most circadian rhythms (2-5); however, some rhythms persist including mitosis in cornea and gut and disk shedding in the retina (6, 7). Circadian rhythms in wheel-running behavior, absent following complete SCN lesions, reappear when methamphetamine is provided chronically to SCN-lesioned rats (8). Furthermore, SCN-lesioned rats express a rhythm in food-anticipatory activity when exposed to restricted feeding and later fasted (9). Collectively, these observations reveal the existence of extra-SCN circadian oscillators. More recent results suggest that they may be present in most mammalian cells and tissues (10,11).Rapid progress in the cloning and identification of clock genes has revealed that these genes are expressed not only in the SCN but in many peripheral tissues as well (12). The recent development of a transgenic rat model allows for the continuous monitoring of Per1 transcription through use of a luciferase reporter (13). By using this methodology, it was discovered that several peripheral structures, as well as extra-SCN brain areas, exhibit circadian oscillations in vitro (13-15). Consequently, there is now direct evidence that the mammalian circadian system is composed of multiple circadian oscillators, a central pacemaker in the SCN, and damped oscillators i...

Resetting of central and peripheral circadian oscillators in aged rats

“…Three recent studies have begun to address whether there are changes in molecular rhythm generation in aged animals. In all three studies Period 1 (Per1) and/or Period 2 (Per2) gene expression rhythms were unaffected in the aged SCN [3,19,37]. However, Kolker and colleagues [19] reported that both Bmal1 and Clock expression in the SCN was reduced in aged hamsters.…”

“…Because aging affects functions regulated by the SCN, it has been suggested that the SCN itself is the primary locus for age-related changes [37]. Indeed, the aged SCN shows a decrease in VIP expression [18], light-induced immediate early gene expression [5,28], and melatonin binding [6].…”

“…Furthermore induction of Per1 in the SCN by a light pulse was also diminished in aged hamsters [19] and rats [3]. Yamazaki et al [37] investigated rhythmicity in areas outside the SCN in rats using Per1-luciferase reporter gene technology. That study reported the intriguing finding that, in vitro, some tissues from old animals were rhythmic while others were not.…”

“…Because some tissues, although capable of rhythmicity in vitro, do not appear to be rhythmic in vivo [37] and there is evidence for a decrease in the amplitude of both the electrical output [4,25,34] and neurotransmitter expression [18], it is possible that the suprachiasmatic nuclei in aged animals is acting as a weak or unreliable Zeitgeber to peripheral oscillators.…”

Age-related changes in neurochemical components and retinal projections of rat intergeniculate leaflet

“…Moreover, SCN have a reduced expression of two major neurochemical constituents, vasoactive intestinal polypeptide (Chee et al 1988;Krajnak et al 1998), and vasopressin (Roozendaal et al 1987;Cayetanot et al 2005), which accounts to a weakening of SCN interconnections, therefore affecting the circadian clock functionality (Engelberth et al 2013). Current data, however, are focused solely on the aging effects on SCN, which brings a limitation to understand the whole process of aging in CTS (Yamazaki et al 2002;Davidson et al 2008). In view of this absence of data concerning effects of aging in IGL, we documented neurochemical and retinal afferent changes in IGL between young, adult, and aged rats based on GAD, ENK, NPY, and CTb immunoreactivity.…”