IMPAIRED EXPRESSION OF THE<i>mPer2</i>CIRCADIAN CLOCK GENE IN THE SUPRACHIASMATIC NUCLEI OF AGING MICE

Weinert, Heike; Weinert, Dietmar; Schurov, Irina; Maywood, Elizabeth S.; Hastings, Michael H.

doi:10.1081/cbi-100103976

Cited by 75 publications

(49 citation statements)

References 11 publications

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“…Age-dependent changes in the circadian gene expression in laboratory rodents and humans have been described extensively. 37,38 An age-dependent difference was found in the case of Per2 mRNA expression 39 ; also Ucp2 expression increased with age. 40 Thus, the phenotype of increased CCl 4 hepatotoxicity regulated by increased Ucp2 levels because of Per2 gene deficiency could reflect the natural phenomena of increasing the sensitivity to toxicant with age in old animals.…”

Section: Discussionmentioning

confidence: 87%

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

Chen

Pang

et al. 2009

The American Journal of Pathology

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Period 2 (Per2) is a key component of the core clock oscillator and is involved in regulating a number of different biological processes and pathways. Here we report that Per2 plays a protective role in carbon tetrachloride (CCl 4 )-induced hepatotoxicity via the modulation of uncoupling protein-2 (Ucp2) gene expression in mice. Hepatic injury after acute CCl 4 injection was monitored in both wild-type and Per2-null mice. At the 12-hour time point after CCl 4 treatment, many more vacuolations were observed in the liver tissues of Per2-null mice whereas fatty tissue degeneration primarily occurred in the liver tissues of wide-type mice. Serum alanine and aspartate aminotransferase activities were elevated in Per2-null mice compared with wide-type mice at 24 hours after CCl 4 treatment, which was in agreement with the observation of significantly larger areas of centrilobular necrosis in the livers of Per2-null mice. A deficit of the Per2 gene enhanced Ucp2 gene expression levels in the liver. As a consequence, intracellular levels of ATP markedly decreased in the liver, allowing increased production of toxic CCl 4 derivatives. The absence of Per2 expression caused a dramatic elevation of Clock expression and influenced Ucp2 through a mechanism that involved a Clock-controlled PPAR-␣ signal transduction pathway. Our studies suggest that the Per2 gene functions in hepatocyte protection from chemical toxicants via the regulation of hepatic

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Section: Discussionmentioning

confidence: 87%

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

Chen

Pang

et al. 2009

The American Journal of Pathology

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“…This suggests that some age-related alterations are because of circadian system changes outside of the SCN or, alternatively, because of changes within the SCN other than the Per1 transcript that we have measured. Very recently, Weinert et al (46) reported that the amplitude of day-night expression of mPer2 but not of mPer1 in the SCN was decreased in aged mice. However, this change in mPer2 amplitude may be species-specific.…”

Section: Discussionmentioning

confidence: 99%

Effects of aging on central and peripheral mammalian clocks

Yamazaki

Straume

Tei

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

282

220

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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...

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“…In aged animals, Per1 expression following an entraining light stimulus is markedly reduced with a significantly longer delay to resynchronization (Davidson et al, 2008;Kolker et al, 2003). In young animals, disruption of the Period genes leads to aging-like declines in sensitivity to light (Asai et al, 2001;Weinert et al, 2001). These findings suggest that temporal disorganization with advancing age may result, in part, from reductions in the sensitivity of the SCN to retinal stimulation.…”

Section: A Aged-related Changes In Circadian Entrainmentmentioning

confidence: 99%

Aging in the circadian system: Considerations for health, disease prevention and longevity

Gibson

Williams

Kriegsfeld

2009

Experimental Gerontology

139

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The circadian system orchestrates internal physiology on a daily schedule to promote optimal health and maximize disease prevention. Chronic disruptions in circadian function are associated with an increase in a variety of disease states including, heart disease, ulcers, and diabetes. With advanced age, the genes regulating circadian function at the cellar level become disorganized and the ability of the brain clock to entrain to local time diminishes. As a result, aged individuals exhibit a loss of temporal coordination among bodily systems, leading to deficits in homeostasis and sub-optimal functioning. Such disruptions in the circadian system appear to accelerate the aging process and contribute to senescence, with some systems being more vulnerable than others. This review explores aging-associated changes in circadian function and examines evidence linking such alterations to adverse health consequences in late life and promotion of the aging process.

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IMPAIRED EXPRESSION OF THEmPer2CIRCADIAN CLOCK GENE IN THE SUPRACHIASMATIC NUCLEI OF AGING MICE

Cited by 75 publications

References 11 publications

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

Effects of aging on central and peripheral mammalian clocks

Aging in the circadian system: Considerations for health, disease prevention and longevity

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